Substituted pyrimidinones as agonists of the apj receptor

ABSTRACT

Compounds of Formula I and Formula II, pharmaceutically acceptable salts thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: Figure I and Figure II where the definitions of the variables are provided herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/665,244, filed on May 1, 2018, which is hereby incorporated byreference in its entirety and for all purposes as if fully set forthherein.

FIELD OF THE INVENTION

The present invention relates to compounds capable of acting as agonistsof the APJ Receptor, and compositions that include compounds that areagonists of the APJ Receptor. The compounds and compositions may be usedto activate the APJ Receptor and to treat various disease conditions. Anexample of one area where such compounds may be used is in the treatmentof cardiovascular conditions. In particular, the compounds may be usedto improve contractility and ejection fraction in subjects with chronicheart failure and may be used to beat patients with heart failure withreduced ejection fraction and patients with heart failure with preservedejection fraction.

BACKGROUND OF THE INVENTION

Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptorlike-1). The APJ receptor is a member of the rhodopsin-like Gprotein-coupled receptor (GPCR) family. The apelin/APJ system has beenobserved in many tissues such as heart, kidney, pancreas, lung and thecentral nervous system. This suggests diverse roles of the system in thephysiology and pathology of mammals.

Apelin peptides are processed from a 77 residue pre-pro form intosmaller bioactive fragments, mainly a 36 residue form (Apelin 42-77—alsoreferred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin65-77—also referred to as Apelin-13) Hosoya et al., J. Biol. Chem.275:21061-21067, 2000. Apelin peptides were previously determined to beendogenous ligands for the orphan APJ receptor, a member of the seventiansmembrane G-protein-coupled receptor superfamily. Tatemoto et al.,Biochem. Biophysi. Res. Commun. 251:471-476, 1998. One of the shortermore active isoforms identified, pyroglutamated apelin-13 ([PE65]Apelin-13 (65-77), has been reported to be the most potent and abundantform of apelin in cardiac tissue. Maguire et al., Hypertension54:598-604, 2009. In vitro and preclinical models have suggested thatthe apelin/APJ system has a role in cardiovascular homeostasis as wellas metabolism. Barnes et al., Heart 96:1011-1016, 2010. Circulatingapelin levels are transient and Apelin-13 has a brief plasma half-lifeof <5 min leading to short-lived cardiovascular effects.

In vitro, exogenous apelin increases contractility at subnanomolarconcentrations in atrial strips and whole rat hearts, and increasessarcomere shortening by up to 140% in isolated cardiomyocyctes. Barneset al., Heart 96:1011-1016, 2010. Apelin also has a potent inotropiceffect in an ex vivo isolated heart assay. In vivo, acute apelininfusion restores ejection fraction, increases cardiac output andreduces left ventricular end-diastolic pressure in rats with chronicheart failure. Berry et al., Circulation 110:187-193, 2004. Exogenousapelin potently enhances myocardial contractility without inducing leftventricular hypertrophy concomitant with reduction in ventricularpreload and afterload. Barnes et al., Heart 96:1011-1016, 2010.

Studies from Kawamata et al and Hosoya et al have shown that thatshorter peptide apelin-13 had approximately a 3.5-fold higher in vitroaffinity to the APJ receptor than apelin-36. Kawamata et al., BBA 1538:162-171, 2001, Hosoya et al., JBC 275: 21061-21067. Apelin-13 analogueswere reported having a single substitution with either canonical ornon-canonical amino acids. The authors also reported double and triplesubstitutions in apelin 66-77 and apelin 63-77, but not in apelin-13.The emphasis was on peptides reported to have higher in vitro affinityand potency than apelin-13. Nishizawa et al., in: T. Shioiri (ed.),Peptide Science 2000: Proceedings of the 37^(th) Japanese PeptideSymposium, pp. 151-154. Several if not all of these modified peptidesare reported in later studies. U.S. Pat. No. 7,635,751.

In a 2003 study (Medhurst et al., J. Neurochemistry 84:1162-1172, 2003)in vitro activity of apelin-36, apelin-17 and apelin-13 was compared. Itwas concluded that all three peptides were approximately equipotent.C-terminal amidation resulted in about a 14-fold decrease in affinity. Amore recent study (Hamada et al., J. Mol. Med. 22:547-552, 2008)reported cyclic analogues of apelin-13. When tested for in vitroactivity all three analogues maintained function activity, although withreduced potency relative to apelin-13.

A shortened 12 amino acid-apelin peptide having ligand activity on APJwas reported in a 2009 patent (U.S. Pat. No. 7,635,751). The peptidecould have a substitution of one non-canonical amino acid. In anotherapplication, WO 2013/111110 A2 and U.S. Pat. No. 8,673,848, cyclicmimetics of apelin have also been reported.

Another study reported synthesizing analogs of apelin-13 with amino acidsubstitutions with non-canonical amino acids at the C-terminal end ofthe molecule, but no pegylation at the N- or C-terminus or another sitespecific location. The use of internal PEG spacers (short PEG (n=4 or6), however, was also reported in lower activity peptide analogs withdeletions in the middle of the sequence that contained fewer amino acidresidues than apelin-13. Murza et al. ChemMedChem 7:318-325, 2012.Additionally, PCT/US2013/075773 describes a group of modifications,including substitution of non-canonical amino acids and changes at theN- and C-terminal of the apelin molecule that can affect, inter alia,the potency of the molecule. The increased potency can be a result ofincreased half-life or decreased degradation relative to wild-typeapelin.

Despite the advancements that have been made with respect to peptides, aneed exists for small molecule agonists of the APJ receptor. However,some progress has been made in this area. For example, WO 2014/044738discloses various benzimidazole-carboxylic acid amide derivatives asmodulators of the APJ Receptor. Other small molecule agonists of the APJreceptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336, WO2016/187308, WO 2015/184011, WO 2015/188073, WO 2016/196771, WO2017/192485, WO 2017/0066402, WO 2017/106396, WO 2017/165640, WO2017/218617, and WO 2017/218633.

A need continues to exist for agonists of the APJ receptor that may beused to treat various cardiovascular and other conditions. The presentapplication discloses such agonists of the APJ receptor s that may besuitable for use as therapeutic agents in treating a variety ofconditions. These compounds may find particular benefit in treatingcardiovascular conditions. For example, such compounds may be beneficialin treating conditions such as chronic systolic heart failure andchronic diastolic heart failure.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I or FormulaII:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,wherein:

R¹ is selected from R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), orR^(1g);

R^(1a) is an unsubstituted C₁-C₈ straight or branched chain alkyl orR^(1a) is a C₁-C₈ straight or branched chain alkyl substituted with 1,2, or 3 R^(1a′) substituents;

R^(1b) is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstitutedC₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, 3, or4 R^(1b′) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with1, 2, or 3 R^(1b′) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1b′) substituents;

R^(1c) is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partiallysaturated heterocyclic group that includes 1, 2, or 3 heteroatomsindependently selected from N, O, or S that is unsubstituted or issubstituted with 1, 2, or 3 R^(1c′) substituents;

R^(1d) is a phenyl group that is unsubstituted or is substituted with 1,2, or 3 R^(1d′) substituents;

R^(1e) is an unsubstituted furanyl, or is a furanyl substituted with 1,2, or 3 R^(1e′) substituents;

R^(1f) is a 5- or 6-membered heteroaryl group that is unsubstituted oris substituted with 1, 2, or 3 R^(1f′) substituents, wherein the5-membered heteroaryl group includes 1, 2, or 3 heteroatomsindependently selected from N, O, and S and the 6-membered heteroarylgroup includes 2 or 3 N heteroatoms; and further wherein if the5-membered heteroaryl includes only 1 hetero atom, then it is selectedfrom N or S;

R^(1g) is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, oris a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3,or 4 R^(1g′) substituents;

R^(1a′) in each instance is independently selected from —F, —Cl, —Br,—I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₂-C₄ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a monocyclic or bicyclic C₆-C₁₀ aryl group,—O-(monocyclic or bicyclic C₆-C₁₀ aryl group), a monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, —O-(monocyclic orbicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S), C₃-C₈ cycloalkyl,—O—(C₃-C₈ cycloalkyl), —O—(C₁-C₆ alkyl)-(C₃-C₈ cycloalkyl), —O—(C₁-C₆alkyl)-(monocyclic or bicyclic C₆-C₁₀ aryl group), O—(C₁-C₆alkyl)-(monocyclic or bicyclic heteroaryl group with 5 to 10 ringmembers containing 1, 2, or 3 heteroatoms independently selected from N,O, or S), a 3 to 8 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, —O-(heterocyclylgroup containing 3 to 8 ring members and 1, 2, or 3 heteroatomsindependently selected from N, O, or S), or an —O—(C₁-C₆alkyl)-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3heteroatoms independently selected from N, O, or S), wherein the C₆-C₁₀aryl of any of the R^(1a′) groups that include a C₆-C₁₀ aryl group, theheteroaryl of any of the R^(1a′) groups that include a heteroaryl group,the C₃-C₈ cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈cycloalkyl group, and the heterocyclyl of any of the R^(1a′) groups thatinclude a heterocyclyl group are unsubstituted or are substituted with1, 2, or 3 R^(1a″) substituents; and further wherein the C₃-C₈cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈ cycloalkylgroup, and the heterocyclyl of any of the R^(1a′) groups that include aheterocyclyl group may additionally be substituted with 1 or 2 oxosubstituents, and the S atom of the heterocyclyl of any of the R^(1a′)groups that include a heterocyclyl group may contain one or two oxosubstituents, and still further wherein, the heteroaryl of any of theR^(1a′) groups that include a heteroaryl group may include an N-oxide ifthe heteroaryl includes a N heteroatom;

R^(1a″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1b′) phenyl and R^(1b′)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1b′) substituents; and further wherein two R^(1b′) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R^(1b) group may jointogether with the carbon atom to which they are attached to form aheterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatomsindependently selected from O, N, and S;

R^(1b″) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R^(1c′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl), wherein R^(1c′) mayalso be oxo unless R^(1c) is a 6-membered heterocyclic group thatincludes one N atom and includes at least one double bond, and furtherwherein two R^(1c′) substituents on adjacent carbon atoms or on anadjacent carbon atom and an adjacent N atom of a 5- or 6-memberedheterocyclic R^(1c) group may join to form a 6 membered ring that may besaturated, partially saturated, or aromatic and may include 0, 1, or 2 Natoms and may further optionally be substituted with 1 or 2 R^(1c″)substituent and may include an oxo substituent if the ring is not anaromatic ring and further wherein two R^(1c′) substituents on adjacentcarbon atoms or on an adjacent carbon atom and an adjacent N atom of a5- or 6-membered heterocyclic R^(1c) group may join to form a 5 memberedring that may be saturated, partially saturated, or aromatic and mayinclude 0, 1, or 2 heteroatoms selected from N, O, or S and may furtheroptionally be substituted with 1 or 2 R^(1c″) substituent and mayinclude an oxo substituent if the ring is not an aromatic ring;

R^(1c″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1d′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl),—S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the—O-phenyl R^(1d′) group may optionally be substituted with 1 or 2R^(1d″) substituents; and further wherein two R^(1d′) substituents onadjacent carbon atoms of the phenyl R^(1d) group may join to form a 5 or6 membered ring that may be saturated, partially saturated, or aromaticand may include 0, 1, 2, or 3 heteroatoms independently selected from N,O, and S and may further optionally be substituted with 1 or 2 R^(1d′″)substituent and may include an oxo substituent if the ring is not anaromatic ring;

R^(1d″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1d′″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or—S(═O)₂—(C₁-C₆ alkyl);

R^(1e′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂;

R^(1f′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), or —CH(OH)-phenyl, wherein the phenyl of the—CH(OH)-phenyl may optionally be substituted with one or two R^(1f″)substituents; and further wherein two R^(1f′) substituents on adjacentcarbon atoms or on an adjacent carbon atom and an adjacent N atom of the5- or 6-membered heteroaryl R^(1f) group may join to form a 5 or 6membered ring that may be saturated, partially saturated, or aromaticand may include 0, 1, 2, or 3 heteroatoms independently selected from N,O, and S and may further optionally be substituted with 1 or 2 R^(1f″)substituent and may include an oxo substituent if the ring is not anaromatic ring;

R^(1f′) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1f″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyO—O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or—S(═O)₂—(C₁-C₆ alkyl);

R^(1g′) in each instance is independently selected from —F, —Cl, —Br,—I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₁-C₆alkyl —OH, —C₁-C₆ haloalkyl-OH, —C₁-C₆ perhaloalkyl-OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl,—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, phenyl, —C(═O)-(heterocyclyl), a C₃-C₆ cycloalkyl group or aheterocyclyl group, wherein the heterocyclyl group of the—C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ringcontaining 1, 2, or 3 heteroatoms selected from N, O, or S;

R² is selected from —H, or C₁-C₄ alkyl;

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkylsubstituted with 1, 2, or 3 R^(3a) substituents, an unsubstituted C₃-C₈cycloalkyl, a C₃-C₈ cycloalkyl substituted with 1, 2, or 3 R^(3a)substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3b)═CR^(3c))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, -Q, a group offormula —(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q,wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ringmembers of which 1, 2, or 3 are heteroatoms independently selected fromN, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3a) in each instance is independently selected from —F, —Cl, —CN,—OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), C₂-C₆ alkenyl,C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic orbicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)₂ phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆,alkyl, or —C(═O)—(O—C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein theheterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a)groups is a 3-6 membered ring comprising 1 or 2 heteroatomsindependently selected from N, O, or S, and is unsaturated or partiallyunsaturated and is optionally substituted with 1 or 2 oxo substituents,and further wherein the heterocyclyl of the R⁴ group may be furthersubstituted with 1 oxo substituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,oxo, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—S—(C₁-C₆ alkyl), —S—(C₁-C₆ haloalkyl), —S—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —C(═O)NH(C₃-C₆cycloalkyl), —C(═O)N(C₁-C₆ alkyl)(C₃-C₆ cycloalkyl), —C(═O)N(C₃-C₆cycloalkyl)₂, —S(═O)—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a 3 to 6membered cycloalkyl group, a 3 to 6 membered heterocyclyl groupcontaining 1 or 2 heteroatoms selected from N, O, or S, a phenyl group,or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatomsselected from N, O, or S, wherein the a 3 to 6 membered cycloalkylR^(4b) group, the 3 to 6 membered heterocyclyl R^(4b) group, the phenylR^(4b) group, and the a 5 or 6 membered heteroaryl R^(4b) ring areunsubstituted or are substituted with 1 or 2 R^(4c) substituents; andfurther wherein the 3 to 6 membered cycloalkyl R^(4b) group and the 3 to6 membered heterocyclyl R^(4b) group may optionally be additionallysubstituted with an oxo substituent; and

R^(4c) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂.

Numerous other embodiments of the compound of Formula I and Formula IIare set forth herein.

Also provided are pharmaceutical compositions that include at least onepharmaceutically acceptable excipient, carrier or diluent and thecompound or the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof accordingto any one of the embodiments.

In other embodiments, the invention provides a method of treating acardiovascular condition. Such methods typically include administeringto a subject an effective amount of the compound or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.In some such embodiments, the cardiovascular condition is heart failure.In some such embodiments, the cardiovascular condition is heart failurewith reduced ejection fraction whereas in other embodiments it is heartfailure with preserved ejection fraction. Thus, in some embodiments, thecardiovascular condition is chronic systolic heart failure or chronicdiastolic heart failure. In other embodiments, the cardiovascularcondition is acute heart failure whereas in other embodiments, thecardiovascular condition is hypertension.

In still other embodiments, the invention provides a method of improvingcardiac contractility in a subject. Such methods typically includeadministering to the subject an effective amount of the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.

In still other embodiments, the invention provides a method ofincreasing ejection fraction in a subject suffering from acardiovascular condition. Such methods typically include administeringto the subject an effective amount of the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.In such embodiments, the ejection fraction is increased in the subjectafter administration.

In still other embodiments, the invention provides a method of treatinga condition in a subject where it is desired to activate the APJReceptor. Such methods typically include administering to the subject aneffective amount of the compound or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof according to any one of the embodiments or a pharmaceuticalcomposition of any of the embodiments. In some such embodiments, thecondition is obesity or diabetes whereas in other such embodiments, thecondition is diabetic nephropathy or chronic kidney disease.

In other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor use in treating a cardiovascular condition. In some suchembodiments, the cardiovascular condition is heart failure. In some suchembodiments, the cardiovascular condition is heart failure with reducedejection fraction whereas in other embodiments it is heart failure withpreserved ejection fraction. Thus, in some embodiments, thecardiovascular condition is chronic systolic heart failure or chronicdiastolic heart failure. In other embodiments, the cardiovascularcondition is acute heart failure whereas in other embodiments, thecardiovascular condition is hypertension.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor improving the cardiac contractility in a subject suffering from acardiovascular condition.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor improving the ejection fraction in a subject suffering from acardiovascular condition.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor treating a condition in a subject where it is desired to activatethe APJ Receptor. In some such embodiments, the condition is obesity ordiabetes whereas in other such embodiments, the condition is diabeticnephropathy or chronic kidney disease.

Other objects, features and advantages of the invention will becomeapparent to those skilled in the art from the following description andclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the humanAPJ-AT1R (angiotensin Type 1) double stable CHO cell line. The functionof the inositol phosphate accumulation (IP1) was measured byTime-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665nm respectively. Addition of pyr apelin-13 induces the positivecooperativity on the AT1R upon activation by APJ receptor.

FIG. 2 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the human APJreceptor expressed in the CHO cell line. The function of the inositolphosphate accumulation (IP 1) was measured by Time-resolved fluorescenceresonance energy (TR-FRET) at 620 nm and 665 nm respectively. There wasno positive cooperativity observed upon treatment with pyr apelin-13when the human APJ receptor is expressed alone.

FIG. 3 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the humanAT1R receptor expressed in the CHO cell line. The function of theinositol phosphate accumulation (IP 1) was measured by Time-resolvedfluorescence resonance energy (TR-FRET) at 620 nm and 665 nmrespectively. There was no positive cooperativity observed when thehuman AT1R receptor is expressed alone by pyr apelin-13 in the absenceof APJ expression.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thestandard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemicalformula, its definition on each occurrence is independent of itsdefinition at every other occurrence. If the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds of the present disclosure maycontain one or more chiral centers and/or double bonds and therefore,may exist as stereoisomers, such as double-bond isomers (i.e., geometricisomers), enantiomers or diastereomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intothe component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.

The term “comprising” is meant to be open ended, i.e., all encompassingand non-limiting. It may be used herein synonymously with “having” or“including”. Comprising is intended to include each and every indicatedor recited component or element(s) while not excluding any othercomponents or elements. For example, if a composition is said tocomprise A and B. This means that the composition has A and B in it, butmay also include C or even C, D, E, and other additional components.

Certain compounds of the invention may possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, enantiomers,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the invention. Furthermore,atropisomers and mixtures thereof such as those resulting fromrestricted rotation about two aromatic or heteroaromatic rings bonded toone another are intended to be encompassed within the scope of theinvention. For example, when R⁴ is a phenyl group and is substitutedwith two groups bonded to the C atoms adjacent to the point ofattachment to the N atom of the pyrmidinone, then rotation of the phenylmay be restricted. In some instances, the barrier of rotation is highenough that the different atropisomers may be separated and isolated.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pine” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the mirror image enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line indicates that both stereoisomers areencompassed. This is not to be confused with a wavy line drawnperpendicular to a bond which indicates the point of attachment of agroup to the rest of the molecule.

As described above, this invention encompasses the use ofstereomerically pine forms of such compounds, as well as the use ofmixtures of those forms. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular compound of theinvention may be used in methods and compositions of the invention.These isomers may be asymmetrically synthesized or resolved usingstandard techniques such as chiral columns or chiral resolving agents.See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions(Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997)Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds(McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agentsand Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972).

As known by those skilled in the art, certain compounds of the inventionmay exist in one or more tautomeric forms. Because one chemicalstructure may only be used to represent one tautomeric form, it will beunderstood that for convenience, referral to a compound of a givenstructural formula includes tautomers of the structure represented bythe structural formula.

Compounds of the invention are depicted structurally and named ascompounds in the “Tautomer A” form. However, it is specificallycontemplated and known that the compounds exist in “Tautomer B” form andthus compounds in “Tautomer B” form are expressly considered to be partof the invention. For this reason, the claims refer to compounds ofFormula I and Formula II. Depending on the compound, some compounds mayexist primarily in one form more than another. Also, depending on thecompound and the energy required to convert one tautomer to the other,some compounds may exist as mixtures at room temperature whereas othersmay be isolated in one tautomeric form or the other. Examples of othertautomers associated with compounds of the invention are those with apyridone group (a pyridinyl) for which hydroxypyridine is a tautomer andcompounds with a ketone group with the enol tautomer. Examples of theseare shown below.

Compounds of the present disclosure include, but are not limited to,compounds of Formula I and Formula II and all pharmaceuticallyacceptable forms thereof. Pharmaceutically acceptable forms of thecompounds recited herein include pharmaceutically acceptable salts,solvates, crystal forms (including polymorphs and clathrates), chelates,non-covalent complexes, prodrugs, and mixtures thereof. In certainembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts. As used herein, the term “compound”encompasses not only the compound itself, but also a pharmaceuticallyacceptable salt thereof, a solvate thereof, a chelate thereof, anon-covalent complex thereof, a prodrug thereof, and mixtures of any ofthe foregoing. In some embodiments, the term “compound” encompasses thecompound itself, pharmaceutically acceptable salts thereof, tautomers ofthe compound, pharmaceutically acceptable salts of the tautomers, andester prodrugs such as (C₁-C₄)alkyl esters. In other embodiments, theterm “compound” encompasses the compound itself, pharmaceuticallyacceptable salts thereof, tautomers of the compound, pharmaceuticallyacceptable salts of the tautomers.

The term “solvate” refers to the compound formed by the interaction of asolvent and a compound. Suitable solvates are pharmaceuticallyacceptable solvates, such as hydrates, including monohydrates andhemi-hydrates.

The compounds of the invention may also contain naturally occurring orunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds areuseful as therapeutic or prophylactic agents, research reagents, e.g.,assay reagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe invention. For example, if a variable is said or shown to be H, thismeans that variable may also be deuterium (D) or tritium (T).

“Alkyl” refers to a saturated branched or straight-chain monovalenthydrocarbon group derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkyl groups include, butare not limited to, methyl, ethyl, propyls such as propan-1-yl andpropan-2-yl, butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. Incertain embodiments, an alkyl group comprises 1 to 20 carbon atoms. Insome embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6carbon atoms whereas in other embodiments, alkyl groups include 1 to 4carbon atoms. In still other embodiments, an alkyl group includes 1 or 2carbon atoms. Branched chain alkyl groups include at least 3 carbonatoms and typically include 3 to 7, or in some embodiments, 3 to 6carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referredto as a (C₁-C₆)alkyl group and an alkyl group having 1 to 4 carbon atomsmay be referred to as a (C₁-C₄)alkyl. This nomenclature may also be usedfor alkyl groups with differing numbers of carbon atoms. The term “alkylmay also be used when an alkyl group is a substituent that is furthersubstituted in which case a bond between a second hydrogen atom and a Catom of the alkyl substituent is replaced with a bond to another atomsuch as, but not limited to, a halogen, or an O, N, or S atom. Forexample, a group —O—(C₁-C₆ alkyl)-OH will be recognized as a group wherean —O atom is bonded to a C₁-C₆ alkyl group and one of the H atomsbonded to a C atom of the C₁-C₆ alkyl group is replaced with a bond tothe O atom of an —OH group. As another example, a group —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl) will be recognized as a group where an —O atom isbonded to a first C₁-C₆ alkyl group and one of the H atoms bonded to a Catom of the first C₁-C₆ alkyl group is replaced with a bond to a secondO atom that is bonded to a second C₁-C₆ alkyl group.

“Alkenyl” refers to an unsaturated branched or straight-chainhydrocarbon group having at least one carbon-carbon double bond derivedby the removal of one hydrogen atom from a single carbon atom of aparent alkene. The group may be in either the Z- or E-form (cis or tram)about the double bond(s). Typical alkenyl groups include, but are notlimited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, andbuta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenylgroup has 2 to 20 carbon atoms and in other embodiments, has 2 to 6carbon atoms. An alkenyl group having 2 to 6 carbon atoms may bereferred to as a (C₂-C₆)alkenyl group.

“Alkynyl” refers to an unsaturated branched or straight-chainhydrocarbon having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and thelike. In certain embodiments, an alkynyl group has 2 to 20 carbon atomsand in other embodiments, has 2 to 6 carbon atoms. An alkynyl grouphaving 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkynylgroup.

“Alkoxy” refers to a radical —OR where R represents an alkyl group asdefined herein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groupsinclude 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atomsin the R group. Alkoxy groups that include 1 to 6 carbon atoms may bedesignated as —O—(C₁-C₆) alkyl or as —O—(C₁-C₆ alkyl) groups. In someembodiments, an alkoxy group may include 1 to 4 carbon atoms and may bedesignated as —O—(C₁-C₄) alkyl or as —O—(C₁-C₄ alkyl) groups group.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl encompasses monocyclic carbocyclic aromaticrings, for example, benzene. Aryl also encompasses bicyclic carbocyclicaromatic ring systems where each of the rings is aromatic, for example,naphthalene. Aryl groups may thus include fused ring systems where eachring is a carbocyclic aromatic ring. In certain embodiments, an arylgroup includes 6 to 10 carbon atoms. Such groups may be referred to asC₆-C₁₀ aryl groups. Aryl, however, does not encompass or overlap in anyway with heteroaryl as separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with an aromatic ring that includesat least one heteroatom, the resulting ring system is a heteroarylgroup, not an aryl group, as defined herein.

“Carbonyl” refers to the radical —C(O) which may also be referred to as—C(═O) group.

“Carboxy” refers to the radical —C(O)OH which may also be referred to as—C(═O)OH.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated cyclic alkyl group derived by theremoval of one hydrogen atom from a single carbon atom of a parentcycloalkane. Typical cycloalkyl groups include, but are not limited to,groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groupsmay be described by the number of carbon atoms in the ring. For example,a cycloalkyl group having 3 to 8 ring members may be referred to as a(C₃-C₈)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may bereferred to as a (C₃-C₇)cycloalkyl and a cycloalkyl group having 4 to 7ring members may be referred to as a (C₄-C₇)cycloalkyl. In certainembodiments, the cycloalkyl group can be a (C₃-C₁₀)cycloalkyl, a(C₃-C₈)cycloalkyl, a (C₃-C₇)cycloalkyl, a (C₃-C₆)cycloalkyl, or a(C₄-C₇)cycloalkyl group and these may be referred to as C₃-C₁₀cycloalkyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkyl, C₃-C₆ cycloalkyl, orC₄-C₇ cycloalkyl groups using alternative language. Cycloalkyl groupsmay be monocyclic or polycyclic. For the purposes of this application,the term “polycyclic” when used with respect to cycloalkyl will includebicyclic cycloalkyl groups such as, but not limited to, norbornane,bicyclo[1.1.1]pentane, and bicyclo[3.1.0]hexane, and cycloalkyl groupswith more ring systems such as, but not limited to, cubane. The term“polycyclic” when used with respect to cycloalkyl will also includespirocyclic ring systems such as, but not limited to, spiro[2.2]pentane,spiro[2.3]hexane, spiro[3.3]heptane, and spiro[3.4]octane.

“Heterocyclyl” and “heterocyclic” refer to a cyclic group that includesat least one saturated, partially unsaturated, but non-aromatic, cyclicring. Heterocyclyl groups include at least one heteroatom as a ringmember. Typical heteroatoms include, O, S and N and are independentlychosen. Heterocyclyl groups include monocyclic ring systems and bicyclicring systems. Bicyclic heterocyclyl groups include at least onenon-aromatic ring with at least one heteroatom ring member that may befused to a cycloalkyl ring or may be fused to an aromatic ring where thearomatic ring may be carbocyclic or may include one or more heteroatoms.The point of attachment of a bicyclic heterocyclyl group may be at thenon-aromatic cyclic ring that includes at least one heteroatom or atanother ring of the heterocyclyl group. For example, a heterocyclylgroup derived by removal of a hydrogen atom from one of the 9 memberedheterocyclic compounds shown below may be attached to the rest of themolecule at the 5-membered ring or at the 6-membered ring.

In some embodiments, a heterocyclyl group includes 5 to 10 ring membersof which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independentlyselected from O, S, or N. In other embodiments, a heterocyclyl groupincludes 3 to 7 ring members of which 1, 2, or 3 heteroatom areindependently selected from O, S, or N. In such 3-7 memberedheterocyclyl groups, only 1 of the ring atoms is a heteroatom when thering includes only 3 members and includes 1 or 2 heteroatoms when thering includes 4 members. In some embodiments, a heterocyclyl groupincludes 3 or 4 ring members of which 1 is a heteroatom selected from O,S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ringmembers of which 1, 2, or 3 are heteroatoms independently selected fromO, S, or N. Typical heterocyclyl groups include, but are not limited to,groups derived from epoxides, aziridine, azetidine, imidazolidine,morpholine, piperazine, piperidine, hexahydropyrimidine,1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine,tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and thelike. Heterocyclyl groups may be fully saturated, but may also includeone or more double bonds. Examples of such heterocyclyl groups include,but are not limited to, 1,2,3,6-tetrahydropyridinyl,3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl,2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like.Substituted heterocyclyl also includes ring systems substituted with oneor more oxo (═O) or oxide (—O⁻) substituents, such as piperidinylN-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl,benzimidazolonyl, benzo[d]oxazol-2(3H)-only,3,4-dihydroisoquinolin-1(2H)-only, indolin-only,1H-imidazo[4,5-c]pyridin-2(3H)-only, 7H-purin-8(9H)-only,imidazolidin-2-only, 1H-imidazol-2(3H)-only,1,1-dioxo-1-thiomorpholinyl, and the like. In heterocyclyl groupcontaining a sulfur atom, the sulfur atom may be bonded to 0, 1, or 2 Oatoms in addition to the adjacent ring members such that the sulfur mayin various oxidation states. For example, a saturated 5-memberedheterocycle containing one heteroatom which is a S may include thefollowing heterocycles.

“Disease” refers to any disease, disorder, condition, symptom, orindication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen isreplaced with a halogen. Thus, the term “haloalkyl” includesmonohaloalkyl (alkyl substituted with one halogen atom) andpolyhaloalkyl (alkyl substituted with two or more halogen atoms).Representative “haloalkyl” groups include difluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term“perhaloalkyl” means, unless otherwise stated, an alkyl group in whicheach of the hydrogen atoms is replaced with a halogen atom. For example,the term “perhaloalkyl”, includes, but is not limited to,trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Heteroaryl groups typically include 5- to14-membered, but more typically include 5- to 10-membered aromatic,monocyclic, bicyclic, and tricyclic rings containing one or more, forexample, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3,heteroatoms chosen from O, S, or N, with the remaining ring atoms beingcarbon. In monocyclic heteroaryl groups, the single ring is aromatic andincludes at least one heteroatom. In some embodiments, a monocyclicheteroaryl group may include 5 or 6 ring members and may include 1, 2,3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1heteroatom where the heteroatom(s) are independently selected from O, S,or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclicheteroaryl groups, at least one of the rings must include a heteroatom,but it is not necessary that both rings include a heteroatom although itis permitted for them to do so. For example, the term “heteroaryl”includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclicaromatic ring or fused to another heteroaromatic ring. In tricyclicaromatic rings, all three of the rings are aromatic and at least one ofthe rings includes at least one heteroatom. For fused, bicyclic andtricyclic heteroaryl ring systems where only one of the rings containsone or more heteroatoms, the point of attachment may be at the ringincluding at least one heteroatom or at a carbocyclic ring. When thetotal number of S and O atoms in the heteroaryl group exceeds 1, thoseheteroatoms are not adjacent to one another. In certain embodiments, thetotal number of S and O atoms in the heteroaryl group is not more than2. In certain embodiments, the total number of S and O atoms in thearomatic heterocycle is not more than 1. Heteroaryl does not encompassor overlap with aryl as defined above. Examples of heteroaryl groupsinclude, but are not limited to, groups derived from acridine,carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine,isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole,2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, and the like. In certain embodiments, the heteroaryl group canbe between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14membered or 5 to 10 membered heteroaryl. In certain embodiments,heteroaryl groups can be those derived from thiophene, pyrrole,benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine,quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

“Pharmaceutically acceptable” refers to generally recognized for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, and the like; or (2) salts formed when an acidicproton present in the parent compound either is replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient” refers to a broad range ofingredients that may be combined with a compound or salt of the presentinvention to prepare a pharmaceutical composition or formulation.Typically, excipients include, but are not limited to, diluents,colorants, vehicles, anti-adherants, glidants, disintegrants, flavoringagents, coatings, binders, sweeteners, lubricants, sorbents,preservatives, and the like.

“Stereoisomer” refers to an isomer that differs in the arrangement ofthe constituent atoms in space. Stereoisomers that are mirror images ofeach other and optically active are termed “enantiomers,” andstereoisomers that are not mirror images of one another and areoptically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject”are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease or disorder, is sufficient toaffect such treatment for the disease, disorder, or symptom. As thoseskilled in the art will recognize this amount is typically not limitedto a single dose, but may comprise multiple dosages over a significantperiod of time as required to bring about a therapeutic or prophylacticresponse in the subject. Thus, a “therapeutically effective amount” isnot limited to the amount in a single capsule or tablet, but may includemore than one capsule or tablet, which is the dose prescribed by aqualified physician or medical care provider. The “therapeuticallyeffective amount” can vary depending on the compound, the disease,disorder, and/or symptoms of the disease or disorder, severity of thedisease, disorder, and/or symptoms of the disease or disorder, the ageof the subject to be treated, and/or the weight of the subject to betreated. An appropriate amount in any given instance can be readilyapparent to those skilled in the art or capable of determination byroutine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, or inhibiting at leastone physical parameter which may not be discernible to the subject.Further, “treating” or “treatment” refers to delaying the onset of thedisease or disorder or at least symptoms thereof in a subject which maybe exposed to or predisposed to a disease or disorder even though thatsubject does not yet experience or display symptoms of the disease ordisorder.

Reference will now be made in detail to embodiments of the presentdisclosure. While certain embodiments of the present disclosure will bedescribed, it will be understood that it is not intended to limit theembodiments of the present disclosure to those described embodiments. Tothe contrary, reference to embodiments of the present disclosure isintended to cover alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the embodiments of the presentdisclosure as defined by the appended claims.

Embodiments

The embodiments listed below are presented in numbered form forconvenience and in ease and clarity of reference in referring back tomultiple embodiments.

In a first embodiment, the invention provides a compound of Formula I orFormula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,wherein:

R¹ is selected from R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), orR^(1g);

R^(1a) is an unsubstituted C₁-C₈ straight or branched chain alkyl orR^(1a) is a C₁-C₈ straight or branched chain alkyl substituted with 1,2, or 3 R^(1a′) substituents;

R^(1b) is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstitutedC₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, 3, or4 R^(1b′) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with1, 2, or 3 R^(1b′) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1b′) substituents;

R^(1c) is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partiallysaturated heterocyclic group that includes 1, 2, or 3 heteroatomsindependently selected from N, O, or S that is unsubstituted or issubstituted with 1, 2, or 3 R^(1c′) substituents;

R^(1d) is a phenyl group that is unsubstituted or is substituted with 1,2, or 3 R^(1d′) substituents;

R^(1e) is an unsubstituted furanyl, or is a furanyl substituted with 1,2, or 3 R^(1e′) substituents;

R^(1f) is a 5- or 6-membered heteroaryl group that is unsubstituted oris substituted with 1, 2, or 3 R^(1f′) substituents, wherein the5-membered heteroaryl group includes 1, 2, or 3 heteroatomsindependently selected from N, O, and S and the 6-membered heteroarylgroup includes 2 or 3 N heteroatoms; and further wherein if the5-membered heteroaryl includes only 1 hetero atom, then it is selectedfrom N or S;

R^(1g) is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, oris a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3,or 4 R^(1g′) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₂-C₄ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a monocyclic or bicyclic C₆-C₁₀ aryl group,—O-(monocyclic or bicyclic C₆-C₁₀ aryl group), a monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, —O-(monocyclic orbicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S), C₃-C₈ cycloalkyl,—O—(C₃-C₈ cycloalkyl), —O—(C₁-C₆ alkyl)-(C₃-C₈ cycloalkyl), —O—(C₁-C₆alkyl)-(monocyclic or bicyclic C₆-C₁₀ aryl group), O—(C₁-C₆alkyl)-(monocyclic or bicyclic heteroaryl group with 5 to 10 ringmembers containing 1, 2, or 3 heteroatoms independently selected from N,O, or S), a 3 to 8 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, —O-(heterocyclylgroup containing 3 to 8 ring members and 1, 2, or 3 heteroatomsindependently selected from N, O, or S), or an —O—(C₁-C₆alkyl)-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3heteroatoms independently selected from N, O, or S), wherein the C₆-C₁₀aryl of any of the R^(1a′) groups that include a C₆-C₁₀ aryl group, theheteroaryl of any of the R^(1a′) groups that include a heteroaryl group,the C₃-C₈ cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈cycloalkyl group, and the heterocyclyl of any of the R^(1a′) groups thatinclude a heterocyclyl group are unsubstituted or are substituted with1, 2, or 3 R^(1a′) substituents; and further wherein the C₃-C₈cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈ cycloalkylgroup, and the heterocyclyl of any of the R^(1a′) groups that include aheterocyclyl group may additionally be substituted with 1 or 2 oxosubstituents, and the S atom of the heterocyclyl of any of the R^(1a′)groups that include a heterocyclyl group may contain one or two oxosubstituents, and still further wherein, the heteroaryl of any of theR^(1a′) groups that include a heteroaryl group may include an N-oxide ifthe heteroaryl includes a N heteroatom;

R^(1a″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b′) in each instance is independently selected from —F, —Cl, —Br,—I, —CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1b′) phenyl and R^(1b′)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1b′) substituents; and further wherein two R^(1b′) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R^(1b) group may jointogether with the carbon atom to which they are attached to form aheterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatomsindependently selected from O, N, and S;

R^(1b″) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R^(1c′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl), wherein R^(1c) mayalso be oxo unless R^(1c) is a 6-membered heterocyclic group thatincludes one N atom and includes at least one double bond, and furtherwherein two R^(1c′) substituents on adjacent carbon atoms or on anadjacent carbon atom and an adjacent N atom of a 5- or 6-memberedheterocyclic R^(1c) group may join to form a 6 membered ring that may besaturated, partially saturated, or aromatic and may include 0, 1, or 2 Natoms and may further optionally be substituted with 1 or 2 R^(1c″)substituent and may include an oxo substituent if the ring is not anaromatic ring and further wherein two R^(1c′) substituents on adjacentcarbon atoms or on an adjacent carbon atom and an adjacent N atom of a5- or 6-membered heterocyclic R^(1c) group may join to form a 5 memberedring that may be saturated, partially saturated, or aromatic and mayinclude 0, 1, or 2 heteroatoms selected from N, O, or S and may furtheroptionally be substituted with 1 or 2 R^(1c″) substituent and mayinclude an oxo substituent if the ring is not an aromatic ring;

R^(1c″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1d′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl),—S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the—O-phenyl R^(1d′) group may optionally be substituted with 1 or 2R^(1d″) substituents; and further wherein two R^(1d′) substituents onadjacent carbon atoms of the phenyl R^(1d) group may join to form a 5 or6 membered ring that may be saturated, partially saturated, or aromaticand may include 0, 1, 2, or 3 heteroatoms independently selected from N,O, and S and may further optionally be substituted with 1 or 2 R^(1d′″)substituent and may include an oxo substituent if the ring is not anaromatic ring;

R^(1d″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1d′″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or—S(═O)₂—(C₁-C₆ alkyl);

R^(1e′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂;

R^(1f′) in each instance is independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), or —CH(OH)-phenyl, wherein the phenyl of the—CH(OH)-phenyl may optionally be substituted with one or two R^(1f′)substituents; and further wherein two R^(1f′) substituents on adjacentcarbon atoms or on an adjacent carbon atom and an adjacent N atom of the5- or 6-membered heteroaryl R^(1f) group may join to form a 5 or 6membered ring that may be saturated, partially saturated, or aromaticand may include 0, 1, 2, or 3 heteroatoms independently selected from N,O, and S and may further optionally be substituted with 1 or 2 R^(1f′)substituent and may include an oxo substituent if the ring is not anaromatic ring;

R^(1f′) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or—S(═O)₂—(C₁-C₆ alkyl);

R^(1f″) is in each instance independently selected from —F, —Cl, —Br,—I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or—S(═O)₂—(C₁-C₆ alkyl);

R^(1g′) in each instance is independently selected from —F, —Cl, —Br,—I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₁-C₆alkyl —OH, —C₁-C₆ haloalkyl-OH, —C₁-C₆ perhaloalkyl-OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl,—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, phenyl, —C(═O)-(heterocyclyl), a C₃-C₆ cycloalkyl group or aheterocyclyl group, wherein the heterocyclyl group of the—C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ringcontaining 1, 2, or 3 heteroatoms selected from N, O, or S;

R² is selected from —H, or C₁-C₄ alkyl;

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkylsubstituted with 1, 2, or 3 R^(3a) substituents, an unsubstituted C₃-C₈cycloalkyl, a C₃-C₈ cycloalkyl substituted with 1, 2, or 3 R^(3a)substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3b)═CR^(3c))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, -Q, a group offormula —(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q,wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ringmembers of which 1, 2, or 3 are heteroatoms independently selected fromN, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3a) in each instance is independently selected from —F, —Cl, —CN,—OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —C₂-C₆ alkenyl,C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic orbicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)_(2j) phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the—(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6membered ring comprising 1 or 2 heteroatoms independently selected fromN, O, or S, and is unsaturated or partially unsaturated and isoptionally substituted with 1 or 2 oxo substituents, and further whereinthe heterocyclyl of the R⁴ group may be further substituted with 1 oxosubstituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,oxo, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—S—(C₁-C₆ alkyl), —S—(C₁-C₆ haloalkyl), —S—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —C(═O)NH(C₃-C₆cycloalkyl), —C(═O)N(C₁-C₆ alkyl)(C₃-C₆ cycloalkyl), —C(═O)N(C₃-C₆cycloalkyl)₂, —S(═O)—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a 3 to 6membered cycloalkyl group, a 3 to 6 membered heterocyclyl groupcontaining 1 or 2 heteroatoms selected from N, O, or S, a phenyl group,or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatomsselected from N, O, or S, wherein the a 3 to 6 membered cycloalkylR^(4b) group, the 3 to 6 membered heterocyclyl R^(4b) group, the phenylR^(4b) group, and the a 5 or 6 membered heteroaryl R^(4b) ring areunsubstituted or are substituted with 1 or 2 R^(4c) substituents; andfurther wherein the 3 to 6 membered cycloalkyl R^(4b) group and the 3 to6 membered heterocyclyl R^(4b) group may optionally be additionallysubstituted with an oxo substituent; and

R^(4c) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), or —C(═O)N(C₁-C₆ alkyl)₂.

2. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1a).

3. The compound of embodiment 2 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1a) is an unsubstituted C₂-C₆ straight or branchedchain alkyl or R^(1a) is a C₁-C₆ straight or branched chain alkylsubstituted with 1, 2, or 3 R^(1a′) substituents, wherein R^(1a′) ineach instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₄alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl).

4. The compound of embodiment 3 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1a) is an unsubstituted C₂-C₆ straight or branchedchain alkyl or R^(1a) is a C₁-C₆ straight or branched chain alkylsubstituted with 1, 2, or 3 R^(1a′) substituents, wherein R^(1a′) ineach instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl).

5. The compound of embodiment 4 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1a) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

6. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1b).

7. The compound of embodiment 6 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1b) is an unsubstituted monocyclic C₃-C₈ cycloalkylor is a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, or 3 R^(1b′)substituents.

8. The compound of embodiment 7 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1b) is an unsubstituted monocyclic C₃-C₆ cycloalkylor is a monocyclic C₃-C₇ cycloalkyl substituted with 1 or 2 R^(1b′)substituents, wherein R^(1b′) in each instance is independently selectedfrom —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, or—C₁-C₆ perhaloalkyl.

9. The compound of embodiment 8 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R^(1b) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

10. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1c).

11. The compound of embodiment 10 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1c) a 5- or 6-membered saturated orpartially saturated heterocyclic group that includes 1, 2, or 3heteroatoms independently selected from N, O, or S that is unsubstitutedor is substituted with 1, 2, or 3 R^(1c′) substituents.

12. The compound of embodiment 10 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1c) a 5- or 6-membered saturated orpartially saturated heterocyclic group that includes 1, 2, or 3heteroatoms independently selected from N, O, or S that is unsubstitutedor is substituted with 1, 2, or 3 R^(1c′) substituents, wherein thesubstituted or unsubstituted R^(1c) is selected from tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, ormorpholinyl.

13. The compound of embodiment 10 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1c) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

14. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1d).

15. The compound of embodiment 14 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1d) is an unsubstituted phenyl or is aphenyl substituted with 1 or 2 R^(1d′) substituents, wherein the R^(1d′)substituents are independently selected from —F, —Cl, —Br, —I, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₆ alkyl), or —S(═O)₂N(C₁-C₆ alkyl)₂.

16. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1c).

17. The compound of embodiment 16 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1e) is an unsubstituted furanyl substitutedwith 1 or 2 R^(1e′) substituents.

18. The compound of embodiment 16 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1e) is an unsubstituted furanyl substitutedwith 1 or 2 R^(1e′) substituents, wherein the R^(1e′) substituents areindependently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN,—OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl).

19. The compound of embodiment 16 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1e) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

20. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1f).

21. The compound of embodiment 20 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1f) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

22. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is R^(1g).

23. The compound of embodiment 22 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1g) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

24. The compound of embodiment 22 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(1g) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

25. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is an unsubstituted C₁-C₁₀alkyl or is a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a)substituents.

26. The compound of embodiment 25 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, or —CH(CH₃)₂.

27. The compound of embodiment 25 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is —CH(CH₃)₂.

28. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is a group of formula agroup of formula —(CR^(3b)R^(3c))-Q.

29. The compound of embodiment 28 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is —CH₂-Q.

30. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is a group of formula agroup of formula -(heterocyclyl)-Q.

31. The compound of embodiment 30 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein the heterocyclyl of the -(heterocyclyl)-Q R³group is a piperidinyl that is unsubstituted or is substituted with 1 or2 R^(3h) substituent.

32. The compound of embodiment 30 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is a group of formula

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

33. The compound of embodiment 30 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is a group of formula

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

34. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is a group of formula -Q.

34. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q.

36. The compound of embodiment 35 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein, R^(3d) andR^(3e) are independently selected from —H, —C₁-C₆ alkyl, —(C₁-C₆alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); and

R^(3f) and R^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆ alkenyl).

37. The compound of embodiment 35 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein,

R^(3d) and R^(3e) are independently selected from —H, or —C₁-C₆ alkyl;and

R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH,or —O—(C₁-C₆ alkyl).

38. The compound of any one of embodiments 35-37 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein at least one of R^(3d),R^(3e), R^(3f), or R^(3g) is not —H.

39. The compound of any one of embodiments 35-37 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein at least one of R^(3d),R^(3e), R^(3f), or R^(3g) is a —C₁-C₆ alkyl.

40. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

41. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

42. The compound of any one of embodiments 1-24 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

43. The compound of any one of embodiments 1-24 or 28-42 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is selected frompyrimidinyl, pyrazinyl, pyridinyl, phenyl, naphthalenyl, or cyclohexylany of which may be unsubstituted or substituted with 1, 2, or 3 R^(Q)substituents.

44. The compound of embodiment 43 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl,pyridinyl, or phenyl any of which may be unsubstituted or substitutedwith 1, 2, or 3 R^(Q) substituents.

45. The compound of embodiment 43 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is an unsubstituted phenyl or is a phenylsubstituted with 1, 2, or 3 R^(Q) substituents.

46. The compound of any one of embodiments 1-24 or 28-42 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is a monocyclicheteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatomsselected from N, O, or S and Q is unsubstituted or is substituted with 1or 2 R^(Q) substituents.

47. The compound of any of embodiments 1-24 or 28-42 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is a pyrimidinylor pyridinyl group and Q is unsubstituted or is substituted with 1, 2,or 3 R^(Q) substituents.

48. The compound of any of embodiments 1-24 or 28-42 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is a pyrimidinylgroup and Q is unsubstituted or is substituted with 1, 2, or 3 R^(Q)substituents.

49. The compound of any one of embodiments 1-24 or 28-48 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R^(Q) in eachinstance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), or —O—(C₁-C₆ perhaloalkyl).

50. The compound of any one of embodiments 1-24 or 28-48 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R^(Q) in eachinstance is independently selected from —F, —Cl, —Br, —CN, or —CH₃.

51. The compound of any one of embodiments 1-24 or 28-42 thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

52. The compound of any one of embodiments 1-24 or 28-42 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

53. The compound of embodiment 52 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

54. The compound of embodiment 52 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

55. The compound of any one of embodiments 1-54 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R² is —H.

56. The compound of any one of embodiments 1-55 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridinyl, orpyrimidinyl, any of which may be unsubstituted or substituted with 1, 2,or 3 R^(4a) substituents.

57. The compound of any one of embodiments 1-56 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(4a) is in each instanceindependently selected from —F, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NH(C₁-C₆ alkyl-OH), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆alkyl)₂.

58. The compound of embodiment 57 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(4a) is in each instance independentlyselected from —CH₃, —F, —Cl, —Br, —CN, —CF₃, —OCH₃, or —OCHF₂.

59. The compound of embodiment 58 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(4a) is in each instance independentlyselected from —F or, —OCH₃.

60. The compound of any one of embodiments 1-55 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

61. The compound of any one of embodiments 1-55 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

62. The compound of any one of embodiments 1-55 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

63. The compound of any one of embodiments 1-55 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R⁴ is a phenyl or pyrimidinylsubstituted with 1 or 2 R^(4a) substituents.

64. The compound of embodiment 63 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein the R^(4a) substituents are —O—(C₁-C₂ alkyl)groups.

65. The compound of embodiment 1, wherein the compound is selected from

orthe pharmaceutically acceptable salt thereof, or the mixture thereof.

66. The compound of embodiment 1, wherein the compound is selected from

orthe pharmaceutically acceptable salt thereof, or the mixture thereof.

67. A pharmaceutical composition, comprising the compound of any one ofembodiments 1-66 or the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof, and atleast one pharmaceutically acceptable excipient.

68. A pharmaceutical composition, comprising the compound of any one ofembodiments 1-68 or the pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

69. The pharmaceutical composition of embodiment 67 or embodiment 68,further comprising a therapeutic agent selected from an α-blocker, aβ-blocker, an angiotensin converting enzyme (ACE) inhibitor, anangiotensin-receptor blocker (ARB), a calcium channel blocker, adiuretic, an inhibitor of the funny current, a myosin activator, or aneutral endopeptidase (NEP) inhibitor.

70. The pharmaceutical composition of embodiment 67 or embodiment 68,further comprising a therapeutic agent selected from an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB).

71. A method of treating a cardiovascular condition, the methodcomprising: administering to a subject an effective amount of thecompound of any one of embodiments 1-66 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof.

72. The method of embodiment 71, wherein the cardiovascular condition isheart failure.

73. The method of embodiment 71, wherein the cardiovascular condition isheart failure with reduced ejection fraction.

74. The method of embodiment 71, wherein the cardiovascular condition isheart failure with preserved ejection fraction.

75. The method of embodiment 71, wherein the cardiovascular condition ischronic systolic heart failure or chronic diastolic heart failure.

76. The method of embodiment 71, wherein the cardiovascular condition isacute heart failure.

77. The method of embodiment 71, wherein the cardiovascular condition ishypertension.

78. A method of improving cardiac contractility in a subject sufferingfrom a cardiovascular condition, the method comprising: administering tothe subject an effective amount of the compound of any one ofembodiments 1-66 or the pharmaceutically acceptable salt thereof, thestereoisomer of any of the foregoing, or the mixture thereof, whereincardiac contractility is improved in the subject after administration.

79. A method of increasing ejection fraction in a subject suffering froma cardiovascular condition, the method comprising: administering to thesubject an effective amount of the compound of any one of embodiments1-66 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture thereof, wherein the ejectionfraction is increased in the subject after administration.

80. A method of beating a condition in a subject where it is desired toactivate the APJ Receptor, the method comprising: administering to thesubject an effective amount of the compound of any one of embodiments1-66 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture.

81. The method of embodiment 80, wherein the condition is obesity ordiabetes.

82. The method of embodiment 80, wherein the condition is diabeticnephropathy or chronic kidney disease.

83. The method of any one of embodiments 71-82, wherein the methodincludes administering at least one additional therapeutic agent to thesubject, wherein the additional therapeutic agent is selected from anα-blocker, a β-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a calcium channelblocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor.

84. The method of any one of embodiments 71-82, wherein the methodincludes administering at least one additional therapeutic agent to thesubject, wherein the additional therapeutic agent is selected from anangiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptorblocker (ARB).

85. A compound of any one of embodiments 1-66 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof for use in treating a cardiovascular condition.

86. The compound of embodiments 85, wherein the cardiovascular conditionis heart failure.

87. The compound of embodiment 85, wherein the cardiovascular conditionis heart failure with reduced ejection fraction.

88. The compound of embodiment 85, wherein the cardiovascular conditionis heart failure with preserved ejection fraction.

89. The compound of embodiment 85, wherein the cardiovascular conditionis chronic systolic heart failure or chronic diastolic heart failure.

90. The compound of embodiment 85, wherein the cardiovascular conditionis acute heart failure.

91. The compound of embodiment 85, wherein the cardiovascular conditionis hypertension.

92. A compound of any one of embodiments 1-66 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof for use in activating the APJ Receptor or fortreating a condition where it is desirable to activate the APJ Receptor.

93. The compound of embodiment 92, wherein the condition is obesity ordiabetes.

94. The compound of embodiment 92, wherein the condition is diabeticnephropathy or chronic kidney disease.

95. A use of the compound of any one of embodiments 1-66 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof in the preparation of a medicament fortreating a cardiovascular condition.

96. The use of embodiment 95, further comprising a therapeutic agentselected from an α-blocker, a β-blocker, an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calciumchannel blocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor.

97. The use of embodiment 95, further comprising a therapeutic agentselected from an angiotensin converting enzyme (ACE) inhibitor or anangiotensin-receptor blocker (ARB).

98. The use of the compound of any one of embodiments 95-97, wherein thecardiovascular condition is heart failure.

99. The use of the compound of any one of embodiments 95-97, wherein thecardiovascular condition is heart failure with reduced ejectionfraction.

100. The use of the compound of any one of embodiments 95-97, whereinthe cardiovascular condition is heart failure with preserved ejectionfraction.

101. The use of the compound of any one of embodiments 95-97, whereinthe cardiovascular condition is chronic systolic heart failure orchronic diastolic heart failure.

102. The use of the compound of any one of embodiments 95-97, whereinthe cardiovascular condition is acute heart failure.

103. The use of the compound of any one of embodiments 95-97, whereinthe cardiovascular condition is hypertension.

104. A use of the compound of any one of embodiments 1-66 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof in the preparation of a medicament foractivating the APJ Receptor or treating a condition where it isdesirable to activate the APJ Receptor.

105. The use of embodiment 104, wherein the condition is obesity ordiabetes.

106. The use of embodiment 104, wherein the condition is diabeticnephropathy or chronic kidney disease.

107. A treatment regimen for a cardiovascular disease, the regimencomprising: the compound of any one of embodiments 1-66 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof.

108. The treatment regimen of embodiment 107, wherein the regimenfurther comprises a therapeutic agent selected from an α-blocker, aβ-blocker, an angiotensin converting enzyme (ACE) inhibitor, anangiotensin-receptor blocker (ARB), a calcium channel blocker, adiuretic, an inhibitor of the funny current, a myosin activator, or aneutral endopeptidase (NEP) inhibitor.

109. The treatment regimen of embodiment 107, wherein the regimenfurther comprises a therapeutic agent selected from an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB).

110. A kit, the kit comprising: the compound of any one of embodiments1-66 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture thereof.

111. The kit of embodiment 110, wherein the kit further comprises atherapeutic agent selected from an α-blocker, a β-blocker, anangiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptorblocker (ARB), a calcium channel blocker, a diuretic, an inhibitor ofthe funny current, a myosin activator, or a neutral endopeptidase (NEP)inhibitor.

112. The kit of embodiment 110, wherein the kit further comprises atherapeutic agent selected from an angiotensin converting enzyme (ACE)inhibitor or an angiotensin-receptor blocker (ARB).

In some embodiments, the compound is a salt. Such salts may be anhydrousor associated with water as a hydrate. In some embodiments, the compoundmay be in a neutral form as a base or an acid.

Also provided are pharmaceutical compositions that include the compoundor the pharmaceutically acceptable salt thereof, the tautomer thereof,the pharmaceutically acceptable salt of the tautomer, the stereoisomerof any of the foregoing, or the mixture thereof according to any one ofthe embodiments and at least one pharmaceutically acceptable excipient,carrier or diluent. In some such embodiments, the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments is present in an amount effective for the treatment of acardiovascular condition or other condition such as obesity or diabetes,for activating the APJ Receptor. In some embodiments, the pharmaceuticalcomposition is formulated for oral delivery whereas in otherembodiments, the pharmaceutical composition is formulated forintravenous delivery. In some embodiments, the pharmaceuticalcomposition is formulated for oral administration once a day or QD, andin some such formulations is a tablet.

In some embodiments, the subject is a mammal. In some such embodiments,the mammal is a rodent. In other such embodiments, the mammal is acanine. In still other embodiments, the subject is a primate and, insome such embodiments, is a human.

The pharmaceutical compositions or formulations for the administrationof the compounds of this invention may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart. All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition, the active object compound is includedin an amount sufficient to produce the desired effect upon the processor condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The compounds of the invention can be administered to provide systemicdistribution of the compound within the patient. Therefore, in someembodiments, the compounds of the invention are administered to producea systemic effect in the body.

As indicated above, the compounds of the invention may be administeredvia oral, mucosal (including sublingual, buccal, rectal, nasal, orvaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In some embodiments, the compounds of the invention areadministered via mucosal (including sublingual, buccal, rectal, nasal,or vaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In other embodiments, the compounds of the invention areadministered via oral administration. In still other embodiments, thecompounds of the invention are not administered via oral administration.

Different therapeutically effective amounts may be applicable fordifferent conditions, as will be readily known by those of ordinaryskill in the art. Similarly, amounts sufficient to treat or prevent suchconditions, but insufficient to cause, or sufficient to reduce, adverseeffects associated with conventional therapies are also encompassed bythe above described dosage amounts and dose frequency schedules.

The compound of the invention, the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof may find use in treating a number of conditions. For example, insome embodiments, the invention comprises methods or uses that includethe use or administration of the compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention, in treating asubject suffering from a cardiovascular condition. In some embodiments,the cardiovascular condition includes, but is not limited to, coronaryheart disease, stroke, heart failure, systolic heart failure, diastolicheart failure, diabetic heart failure, heart failure with preservedejection fraction, heart failure with reduced ejection fraction,cardiomyopathy, myocardial infarction, myocardial remodeling aftercardiac surgery, valvular heart disease, hypertension including,essential hypertension, pulmonary hypertension, portal hypertension,systolic hypertension, aortic aneurysm such as abdominal aorticaneurysm, or atrial fibrillation including improving arrhythmia. In someembodiments, the cardiovascular condition is heart failure. In some suchembodiments, the heart failure is heart failure with reduced ejectionfraction whereas in other embodiments it is heart failure with preservedejection fraction. In other such embodiments the subject may havesystolic heart failure or chronic diastolic heart failure and is thususeful in treating heart failure patients with systolic dysfunction andin treating heart failure patients with diastolic dysfunction. In someembodiments, the cardiovascular condition may be acute heart failurewhereas in other embodiments, the cardiovascular condition ishypertension.

As noted, the compounds of the invention may be used to beat a number ofdiseases and disorders. Thus, in some embodiments, the inventionprovides a method of beating a disease or disorder selected from acutedecompensated heart failure, chronic heart failure, pulmonaryhypertension, atrial fibrillation, Brugada syndrome, ventriculartachycardia, atherosclerosis, hypertension, restenosis, ischemiccardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia,water retention, diabetes, gestational diabetes, obesity, peripheralarterial disease, cerebrovascular accidents, transient ischemic attacks,traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries,sunburn, edema, and preeclampsia in a subject. Such methods includeadministering a compound of the invention, a pharmaceutically acceptablesalt thereof, a tautomer thereof, a pharmaceutically acceptable salt ofthe tautomer, a stereoisomer of any of the foregoing, a mixture thereof,or a pharmaceutical composition that includes any of these to a subjectin need thereof.

In some embodiments, the invention provides a method of improvingcardiac contractility in a subject suffering from a cardiovascularcondition which includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in cardiac contraction may lead to significantimprovements in methods for beating heart failure patients.

In some embodiments, the invention provides a method of improvingcardiac relaxation in a subject suffering from a cardiovascularcondition which includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in cardiac relaxation may lead to significantimprovements in methods for beating heart failure patients.

In some embodiments, the invention provides a method of improvingventricular arterial coupling in a subject suffering from acardiovascular condition which includes administration of the compound,the pharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in ventricular arterial coupling may lead tosignificant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of increasingejection fraction in a subject suffering from a cardiovascular conditionwhich includes administration of the compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention to the subject.

The compounds of the invention may also find potential benefit inimproving cardiac relaxation and thus find utility in treating certainheart failure patients. The compounds of the invention may thus findutility in improving inotropic function in some embodiments and may alsofind utility in improving lusitropic function.

In some embodiments, the invention provides a method of treatingcondition in a subject where it is desired to activate the APJ Receptor.Such methods include administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. In some such embodiments, the condition is obesity or diabeteswhereas in other embodiments, the condition is diabetic nephropathy orchronic kidney disease. In some such embodiments, the condition is typeII diabetes. In other embodiments, the condition is cardiac wasting.

The compounds of the invention may find utility in treating a number ofother conditions. For example, the compounds of the invention may findutility in treating patients with conditions related to renal perfusion,hyperglycemia, aquaresis, and diuresis. In some embodiments, theinvention provides a method of treating one of these subjects thatincludes administration of the compound, the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof of the invention to the subject. The compounds of theinvention may further find utility in arginine vasopressin (AVP)regulation and in angiotensin receptor (AT1R) regulation.

The compounds of the invention may find utility in treating a number ofother conditions or producing desired outcomes or results. For example,the compounds of the invention may find utility in activating stemcells, more specifically cardiac stem cells, and even more specificallyendogenous cardiac stem cells. Thus, the compounds of the invention mayfind utility in activating heart stem cells in a subject such as in ahuman patient. The compounds of the invention may yet further findutility in regrowing tissue and in assisting functional recovery aftertransplanting cells such as cells with bone marrow-derived mesenchymalstem cells. The compounds of the invention may also find utility inincreasing cardiac stem cell proliferation and may be used to do such inpatients that have suffered a myocardial infarction. As another example,the compounds of the invention may find utility in reducing infarctsize, in promoting cardiac repair, and in activating stem cells andprogenitors in post-myocardial infarction subjects. As still yet anotherexample, the compounds of the invention may be used during surgery suchas heart bypass surgery or heart transplant procedures as a therapeuticto reduce reperfusion injury. In some embodiments, the inventionprovides a method of treating one of these subjects or improving thecondition in a subject that includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject.

Some methods of the invention comprise the administration of a compoundof the invention and an additional therapeutic agent (i.e., atherapeutic agent other than a compound of the invention). Thus, thecompounds of the invention can be used in combination with at least oneother therapeutic agent. Examples of additional therapeutic agentsinclude, but are not limited to, antibiotics, anti-emetic agents,antidepressants, antifungal agents, anti-inflammatory agents,antineoplastic agents, antiviral agents, cytotoxic agents, and otheranticancer agents, immunomodulatory agents, alpha-interferons,β-interferons, alkylating agents, hormones, and cytokines. In oneembodiment, the invention encompasses administration of an additionaltherapeutic agent that is used to treat subjects with chronic heartfailure or hypertension.

As described above some methods of the invention comprise theadministration of a compound of the invention and an additionaltherapeutic agent (i.e., a therapeutic agent other than a compound ofthe invention). In some embodiments, the invention encompassesadministration of an additional therapeutic agent that is used to treatsubjects with chronic heart failure or hypertension. In someembodiments, the invention comprises methods or uses that include theuse of a compound, the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof of theinvention and a therapeutic agent such as, but not limited to, anα-blocker, a β-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a calcium channelblocker, a diuretic, an inhibitor of the funny current, a myosinactivator, a neutral endopeptidase (NEP) inhibitor, a vasodilator, analdosterone antagonist, a natriuretic, a saluretic, a centrally actinghypertensive, an aldosterone synthase inhibitor, or an endothelinreceptor antagonist. In some embodiments, the invention comprisesmethods or uses that include the use of a compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention and a therapeuticagent selected from an α-blocker, a β-blocker, an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calciumchannel blocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor. In some suchembodiments, the invention includes a method that includes administeringa compound of the invention, the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof and an additional therapeutic agent such as an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB). In some such embodiments, the additional therapeutic agent isthus an angiotensin converting enzyme (ACE) inhibitor whereas in othersit is an angiotensin-receptor blocker (ARB). In other such embodiments,the invention includes a method that includes administering a compoundof the invention, the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof and anadditional therapeutic agent such as a neutral endopeptidase (NEP)inhibitor. In other such embodiments, the invention includes a methodthat includes administering a compound of the invention, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof and an additionaltherapeutic agent such as an inhibitor of the funny current. In someembodiments, the method of use may include two or more additionaltherapeutic agents. For example, in some embodiments, the invention mayinclude a compound of the invention, the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof and additional therapeutic agents such as an ACEinhibitor and a NEP inhibitor.

Therapeutic agents such as α-blockers may be used in conjunction withthe compounds of the invention. Examples of α-blockers include, but arenot limited to, doxazosin, prazosin, tamsulosin, and terazosin and theirpharmaceutically acceptable salts.

Therapeutic agents such as β-blockers may be used in conjunction withthe compounds of the invention. Examples of β-blockers include, but arenot limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol,carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol,nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, andtheir pharmaceutically acceptable salts.

Calcium channel blockers may also be used as therapeutic agents inconjunctions with the compounds of the present invention. Examples ofcalcium channel blockers, include, but are not limited to,dihydropyridines (DHPs) and non-DHPs. Examples of DHPs include, but arenot limited to, amlodipine, felodipine, isradipine, lacidipine,nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine,nisoldipine, nitrendipine, nivaldipine, ryosidine, and theirpharmaceutically acceptable salts. Examples of Non-DHPs include, but arenot limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil,mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceuticallyacceptable salts.

Diuretics may also be used in conjunction with the compounds of thepresent invention. Examples include, but are not limited to, thiazidederivatives such as, but not limited to, amiloride, chlorothalidon,chlorothiazide, hydrochlorthiazide, and methylchlorothiazide andpharmaceutically acceptable salts thereof.

Centrally acting hypertensive agents may also be used in conjunctionwith the compounds of the present invention. Examples, include, but arenot limited to, clonidine, guanabenz, guanfacine, methyldopa, andpharmaceutically acceptable salts thereof.

ACE inhibitors may be used in conjunction with the compounds of thepresent invention. Examples of ACE inhibitors that may be used include,but are not limited to, alaceptril, benazepril, benazaprilat, captopril,ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril,Lisinopril, moexipiril, moveltopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril,and zofenopril and their pharmaceutically acceptable salts. Examples ofsome dual ACE/NEP inhibitors include, but are not limited toomapatrilat, fasidotril, and fasidotrilat and their pharmaceuticallyacceptable salts.

ARBs may also be used as therapeutic agents in conjunction with thecompounds of the present invention. Examples of ARBs include, but arenot limited to, candesartan, eprosartan, irbesartan, losartan,olmesartan, tasosartan, telmisartan, and valsartan and theirpharmaceutically acceptable salts. Examples of some dual ARB/NEPinhibitors include, but are not limited to combinations of valsartan andsacubitril and their pharmaceutically acceptable salts.

NEP inhibitors may also be used as therapeutic agents in conjunctionwith the compounds of the present invention. An example of a NEPinhibitor includes, but it not limited to, sacubitril and itspharmaceutically acceptable salts.

Aldosterone synthase inhibitors may also be used as therapeutic agentsin combination with the compounds of the present invention. Examples ofaldosterone synthase inhibitors include, but are not limited to,anastrozole, fadrozole, and exemestane and their pharmaceuticallyacceptable salts.

Endothelin antagonists are other therapeutic agents that may be used inconjunction with the compounds of the present invention. Examplesinclude, but are not limited to, bosentan, enrasentan, atrasentan,darusentan, macitentan, sitaxentan, and tezosentan, and theirpharmaceutically acceptable salts.

Inhibitors of the funny current (I_(f)) may also be used in conjunctionwith the compounds of the invention. An example of an inhibitor of thefunny current is ivabradine and its pharmaceutically acceptable salts.

Myosin activators may also be used in conjunction with the compounds ofthe invention. Examples of myosin activators include cardiac myosinactivators.

It will be recognized that for purposes of this application, atherapeutic agent other than one of the present invention includescompounds such as known prodrugs that are converted into the therapeuticagent after administration. For example, a compound withoutantineoplastic activity, but that is converted into an antineoplasticagent in the body after administration, may be administered along with acompound of the invention. As another example, sacubitril is considereda NEP inhibitor for the purposes of this application even though it is aprodrug that is converted into sacubitrilat by de-ethylation viaesterases.

When administered as a combination, the therapeutic agents can beformulated as separate compositions that are administered at the sametime or sequentially at different times, or the therapeutic agents canbe given as a single composition. The phrase “co-therapy” (or“combination-therapy”), in defining use of a compound of the presentinvention and another pharmaceutical agent, is intended to embraceadministration of each agent in a sequential manner in a regimen thatwill provide beneficial effects of the drug combination, and is intendedas well to embrace co-administration of these agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofthese active agents or in multiple, separate capsules for each agent.Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of cardiovascular conditions.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof any of the embodiments described herein may also be administeredsequentially with known agents for use in treating cardiovascularconditions such as heart failure and hypertension when a combinationformulation is inappropriate. The invention is not limited in thesequence of administration as compounds of the invention may beadministered either prior to, simultaneous with, or after administrationof a known therapeutic agent.

The invention is further described by reference to the followingexamples, which are intended to exemplify the claimed invention but notto limit it in any way.

EXAMPLES

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen or argon atmosphere. Purity was measuredusing Agilent 1100 Series high performance liquid chromatography (HPLC)systems with UV detection at 254 nm and 215 nm (System A: Agilent ZorbaxEclipse XDB-C8 4.6×150 mm, 5 micron, 5 to 100% ACN in H₂O with 0.1% TFAfor 15 min at 1.5 mL/min; System B: Zorbax SB-C8, 4.6×75 mm, 10 to 90%ACN in H₂O with 0.1% formic acid for 12 min at 1.0 mL/min). Silica gelchromatography was generally performed with prepacked silica gelcartridges (Biotage or Teledyne-Isco). ¹H NMR spectra were recorded on aBruker AV-400 (400 MHz) spectrometer or a Varian 400 MHz spectrometer atambient temperature, or the NMR spectra were collected with a BrukerAvance III spectrometer operating at a proton frequency of 500.13 MHzusing a 10 μL Protasis CapNMR flow probe. NMR samples were delivered tothe flow probe using a Protasis One-Minute NMR™ Automation systemcomprised of a Discovery Tower™ Sample Manager and a Waters LiquidHandler made by CTC, Switzerland (Model 2777). All observed protons arereported as parts per million (ppm) downfield from tetramethylsilane(TMS) or another internal reference in the appropriate solventindicated. Data are reported as follows: chemical shift, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet),coupling constants, and number of protons. Low-resolution mass spectral(MS) data were determined on an Agilent 1100 Series LC-MS with UVdetection at 254 nm and 215 nm and a low resonance electrospray mode(ESI).

A wide variety of sulfonamide tails and R⁴ groups can be used tosynthesize compounds of the invention such as those set forth in WO2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which arehereby incorporated by reference in their entireties and for allpurposes as if specifically set forth herein. Thus, compounds of thepresent invention may be prepared using any of the R³, R⁴, and Q groupstaught in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336.

The following Abbreviations are used to refer to various reagents andsolvents:

d day or days

DCM Dichloromethane DMF N,N-Dimethylformamide DMSO DimethylsulfoxideEtOAc Ethyl Acetate EtOH Ethanol

h hour or horns

IPA Isopropanol

min minute or minutes

MeOH Methanol

MS Mass spectrumRT Room temperatureSFC Supercritical fluid chromatography

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran TFC Thin Layer Chromatography Example 4.0.Preparation ofN-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)ethane-1-sulfonamide

N-(2,6-Dimethoxyphenyl)pentanimidamide, Intermediate 1.0. A solution of2,6-dimethoxyaniline (60.0 g, 392.0 mmol) and pentanenitrile (130.0 g,1567.0 mmol) in toluene (1560.0 mL) was cooled to 0° C. under anatmosphere of nitrogen. Trimethylaluminum (392.0 mL, 784.0 mmol) wasthen added dropwise over 30 min and the internal temperature wasmaintained at 0° C. The reaction mixture was warmed to RT and heated to110° C. After 16 h, the mixture was cooled to −10° C. and quenched withcareful addition of a saturated aqueous solution of Rochelle's salt (1.0L) over 30 min. The layers were separated and the aqueous layer wasextracted with EtOAc (2×500 mL). The combined organic layer was washedwith brine (500 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. Purification by columnchromatography (silica gel (60-120 mesh) column, eluting with 5 to 10%MeOH in DCM with added 0.5% TEA) gave Intermediate 1.0 (70.0 g, 296.0mmol). ¹H NMR (400 MHz, CDCl₃) δ 7.04 (t, J=8.3 Hz, 1H), 6.60 (d, J=8.3Hz, 2H), 4.65 (bs, 2H), 3.80 (m, 6H), 2.47-2.24 (m, 2H), 1.70-1.59 (m,2H), 1.50-1.29 (m, 2H), 0.95 (dd, J=6.8 Hz, 3H). LCMS-ESI (pos.) m/z:237.2 (M+H)⁺.

2-Butyl-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one,Intermediate 2.0. A solution of Intermediate 1.0 (80.0 g, 338.5 mmol)and diethyl malonate (516.0 mL, 3385.0 mmol) in 1-butanol (1.2 L) wasstirred at 0° C. under an atmosphere of nitrogen. Sodium hydride (60%dispersion in oil, 135.0 g, 3385.0 mmol) was added portionwise over 90min to maintain an internal temperature of 0° C. The reaction mixturewas warmed to RT and then heated to 100° C. After 16 h, the reactionmixture was cooled to 0° C. and quenched with addition water (1.0 L) andthe resulting solution was concentrated under reduced pressure. Theaqueous layer was acidified with aqueous 1.5N HCl and extracted withEtOAc (2×1.0 L). The combined organic layers were washed with brine (500mL), dried over anhydrous sodium sulphate, filtered and concentratedunder reduced pressure. The residue was diluted with EtOAc (200 mL) andstirred for 15 mins. The resulting white precipitate was collected byvacuum filtration and dried under vacuum to provide Intermediate 2.0(48.0 g, 158.0 mmol0, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (bs,1H), 7.44 (t, J=8.5 Hz, 1H), 6.82 (dd, J=8.6, 3.2 Hz, 2H), 5.25 (s, 1H),3.74 (m, 6H), 2.17 (t, J=7.5 Hz, 2H), 1.58-1.24 (m, 2H), 1.15 (h, J=7.5Hz, 2H), 0.71 (t, J=7.3 Hz, 3H). LCMS-ESI (pos.) m/z: 305.2 (M+H)⁺.

5-Bromo-2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one,Intermediate 3.0. To a solution of Intermediate 2.0 (48.0 g, 158.0 mmol)in DCM (480.0 mL) at 0° C., was added N-bromosuccinimide (28.1 g, 158.0mmol) portionwise. The reaction mixture was warmed to RT and stirred.After 2 h, the reaction mixture was diluted with water (150 mL) and thelayers were separated. The organic layer was washed with brine (150 mL),dried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure. Purification by column chromatography (silica gel(60-120 mesh), eluting 0-10% MeOH in DCM) provided Intermediate 3.0(48.0 g, 125.0 mmol, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s,1H), 7.48 (t, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 3.76 (m, 6H),2.31-2.11 (m, 2H), 1.56-1.34 (m, 2H), 1.15 (h, J=13 Hz, 2H), 0.71 (t,J=7.3 Hz, 3H). LCMS-ESI (pos.) m/z: 383.0 (M+H)⁺.

N-(2-Butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)ethane-1-sulfonamide,Example 4.0. A vial containing Intermediate 5.0 (127 mg, 0.619 mmol),Intermediate 3.0 (356 mg, 0.930 mmol), copper (I) iodide (66.4 mg, 0.349mmol), (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.200 mL, 1.27mmol), and cesium carbonate (612 mg, 1.88 mmol) was degassed andbackfilled with nitrogen (three times). Anhydrous 1,4-dioxane (2.5 mL)was added and the mixture was stirred at 80° C. After 16 h, the reactionwas cooled to RT and diluted with water. The mixture was neutralized bydropwise addition of aqueous 1N HCl (pH 7). The mixture was extractedwith DCM (4×) and the organic layers were combined and washed with 1Msodium thiosulfate (1×). The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.Purification by column chromatography (silica gel, eluting 0-25% 3:1EtOAc: EtOH in DCM) gave the desired product that was further purifiedby preparative SFC method (Column: Chiralpak IC (2×25 cm), Mobile Phase:60:40 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 220 nm, 100bar inlet pressure) to yield Example 4.0. ¹H NMR (400 MHz, DMSO-d₆) δ12.16-11.67 (m, 1H), 8.80 (d, J=0.8 Hz, 2H), 8.38 (br s, 1H), 7.44 (t,J=8.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 3.73 (m, 6H), 3.61-3.55 (m, 2H),3.42-3.36 (m, 2H), 2.19 (t, J=7.7 Hz, 2H), 1.43 (quin, J=7.5 Hz, 2H),1.23-1.10 (m, J=7.3 Hz, 2H), 0.70 (t, J=7.3 Hz, 3H). LCMS-ESI (pos.)m/z: 508.1 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure described in Example 4.0 using the knownstarting material as described.

TABLE 1 Example Reagents Structure, Name and Data 4.15-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one(Intermediate 3.0), isopropylsulfonamide (Nanjing King-Pharm Co., Ltd).Purification was performed by flash chromatography (0-25% 3:1 EtOAc:EtOH in DCM) followed by preparative SFC method (Column: Regis Whelk-Os,s IC (2 × 25 cm), Mobile Phase: 70:30 (A:B) A: Liquid CO₂, B: MeOH,

Flow Rate: 80 mL/min, 220 nm,N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy- 100 bar inlet pressure).6-oxo-1,6-dihydropyrimidin-5-yl)propane-2- The resulting solid was thensulfonamide. triturated from MeOH. ¹H NMR (500 MHz, DMSO-d₆) δ12.02-11.35 (m, 1H), 8.21-7.91 (m, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.84(d, J = 8.6 Hz, 2H), 3.74 (s, 6H), 3.30- 3.27 (m, 1H), 2.19 (br t, J =7.7 Hz, 2H), 1.43 (quin, J = 7.5 Hz, 2H), 1.30-1.23 (m, J = 6.7 Hz, 6H),1.23-1.10 (m, J = 7.4 Hz, 2H), 0.71 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.)m/z: 426.2 (M + H)⁺. 4.2 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0) (2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-2- sulfonamide (Intermediate 5.1).Purification was performed by flash chromatography (0-30% 3:1 EtOAc:EtOH in DCM) followed by preparative HPLC: 50 u Silica Gel 19 × 100 mm +XSelect CSH Prep C18 10 u ODB 19 × 100 mm, A: Water 0.1% formic acid B:ACN 0.1% formic acid, Gradient:

20% (2 min), 20-70% (12 min),(2S,3R)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4- Flow Rate: 40 mL/min,monitored hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-3-(5- @ 215 mn.fluoropyrimidin-2-yl)butane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ11.78 (br s, 1H), 8.80 (d, J = 0.8 Hz, 2H), 8.12 (br s, 1H), 7.43 (t, J= 8.4 Hz, 1H), 6.87-6.79 (m, 2H), 3.91-3.84 (m, 1H), 3.80 (dq, J = 4.0,7.0 Hz, 1H), 3.76-3.68 (m, 6H), 2.16 (br t, J = 7.7 Hz, 2H), 1.43 (td, J= 7.5, 15.2 Hz, 2H), 1.32 (d, J = 7.0 Hz, 3H), 1.27 (d, J = 6.7 Hz, 3H),1.18-1.10 (m, 2H), 0.70 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 536.2(M + H)⁺. 4.3 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0), phenylmethanesulfonamide(Frontier Scientific Services Inc). Purification was performed by flashchromatography (5-25% 3:1 EtOAc: EtOH in DCM) followed by preparativeHPLC: 50 u Silica Gel 19 × 100 mm + XSelect CSH Prep C18 10 u ODB 19 ×100 mm, A: Water 0.1% formic acid B:

ACN 0.1% formic acid, Gradient:N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy- 20% (2 min), 20-70% (12min), 6-oxo-1,6-dihydropyrimidin-5-yl)-1- Flow Rate: 40 mL/min,monitored phenylmethanesulfonamidesulfonamide. @ 215 nm. ¹H NMR (500MHz, DMSO-d₆) δ 11.99 (br s, 1H), 8.20 (br s, 1H), 7.50-7.39 (m, 3H),7.37- 7.29 (m, 3H), 6.86 (d, J = 8.3 Hz, 2H), 4.44 (s, 2H), 3.83-3.74(m, 6H), 2.23 (t, J = 7.7 Hz, 2H), 1.46 (quin, J = 7.5 Hz, 2H),1.22-1.12 (m, 2H), 0.72 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 474.2(M + H)⁺. 4.4a 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0), benzenesulfonamide (AcrosOrganics). Purification was performed using the method described inExample 4.3.

N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5- yl)benzenesulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 11.71 (br s, 1H), 8.63 (br s, 1H), 7.83-7.78 (m, 2H), 7.54-7.48 (m, 1H), 7.47-7.39 (m, 3H), 6.80 (d, J = 8.6 Hz, 2H), 3.75-3.69 (m,6H), 2.15 (t, J = 7.7 Hz, 2H), 1.42 (quin, J = 7.5 Hz, 2H), 1.18-1.10(m, 2H), 0.70 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 460.1 (M + H)⁺.4.4b 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0), 2-phenylethane-1-sulfonamide (Enamine). Purification was perfomed by flashchromatography (0-20% 3:1 EtOAc: EtOH in DCM).

N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2- phenylethane-1-sulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 7.46 (t, J = 8.4 Hz, 1H), 7.31-7.16 (m, 5H), 6.84(d, J = 8.6 Hz, 2H), 3.75-3.68 (m, 6H), 3.34-3.22 (m, 2H), 3.15-3.00 (m,2H), 2.26-2.14 (m, 2H), 1.45 (quin, J = 7.5 Hz, 2H), 1.16 (qd, J = 7.4,14.8 Hz, 2H), 0.72 (t, J = 7.3 Hz, 3H), 2 protons not observed. LCMS-ESI(pos.) m/z: 488.0 (M + H)⁺. 4.5 5-bromo-2-butyl-3-(2,6-dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one (Intermediate 3.0),(R)-2-(5- fluoropyrimidin-2-yl)propane-1- sulfonamide or (S)-2-(5-fluoropyrimidin-2-yl)propane-1- sulfonamide (Intermediate 5.2).Purification was performed by flash chromatography (0-10% MeOH in DCM)followed by preparative HPLC: 50 u Silica Gel 19 × 100 mm + XSelect CSHPrep C18 10 u ODB 19 × 100 mm, A: Water 0.1% formic acid B: ACN 0.1%formic acid, Gradient: 20% (2 min), 20-70% (12 min), Flow Rate: 40mL/min, monitored @ 215 nm.

 

(R)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or(S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ11.85 (br s, 1H), 8.81 (d, J = 0.8 Hz, 2H), 8.28 (br s, 1H), 7.45 (t, J= 8.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 3.80- 3.75 (m, 4H), 3.75-3.73(m, 3H), 3.71-3.64 (m, 1H), 3.38 (dd, J = 5.7, 14.0 Hz, 1H), 2.19 (t, J= 7.7 Hz, 2H), 1.44 (quin, J = 7.5 Hz, 2H), 1.30 (d, J = 7.0 Hz, 3H),1.20-1.11 (m, J = 7.4 Hz, 2H), 0.71 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.)m/z: 522.2 (M + H)⁺. 4.6 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0), (S)-2-(5-fluoropyrimidin-2-yl)propane-1- sulfonamide or (R)-2-(5-fluoropyrimidin-2-yl)propane-1- sulfonamide (Intermediate 5.3).Purification was perfomed by flash chromatography (0-3% MeOH in DCM).

(S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or(R)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ=11.85 (br s, 1H), 8.82 (s, 2H), 8.31 (br s, 1H), 7.46 (t, J = 8.4 Hz,1H), 6.85 (d, J = 8.3 Hz, 2H), 3.80-3.75 (m, 4H), 3.75 (s, 3H),3.72-3.63 (m, 1H), 3.39 (dd, J = 5.7, 14.0 Hz, 1H), 2.51 (td, J = 1.8,3.8 Hz, 2H), 2.26-2.15 (m, 2H), 1.45 (quin, J = 7.5 Hz, 2H), 1.31 (d, J= 7.0 Hz, 3H), 1.20-1.13 (m, J = 7.4 Hz, 2H), 0.72 (t, J = 7.3 Hz, 3H).LCMS-ESI (pos.) m/z: 522.0 (M + H)⁺. 4.7 5-bromo-2-butyl-3-(2,6-dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one (Intermediate 3.0),(R)-2-(5- fluoropyrimidin-2-yl)propane-1- sulfonamide or (S)-2-(5-fluoropyrimidin-2-yl)propane-1- sulfonamide (Intermediate 5.4). Thepurification was performed using the method in Example 4.2.

(S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide or(R)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 8.43 (s, 2H), 8.32 (br s, 1H), 7.43 (t, J = 8.4 Hz, 1H), 6.82 (dd, J =2.9, 8.6 Hz, 2H), 4.99-4.94 (m, 1H), 4.50 (br d, J = 12.5 Hz, 1H), 3.71(s, 3H), 3.65 (s, 3H), 3.20 (tt, J = 3.6, 11.3 Hz, 1H), 3.06-3.00 (m,1H), 2.84- 2.77 (m, 1H), 2.43-2.36 (m, 1H), 2.18 (br t, J = 7.7 Hz, 2H),1.80-1.68 (m, 2H), 1.43 (quin, J = 7.5 Hz, 2H), 1.38-1.28 (m, 1H),1.19-1.11 (m, J = 7.4 Hz, 2H), 0.70 (t, J = 7.4 Hz, 3H). LCMS-ESI (pos.)m/z: 563.2 (M + H)⁺. 4.8 5-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxypyrimidin-4(3H)-one (Intermediate 3.0), (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2- yl)propane-2-sulfonamide (Intermediate5.5). The purification was performed using the method in Example 4.5.

(1R,2S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide. ¹H NMR (500MHz, DMSO-d₆) δ 8.65-8.60 (m, 2H), 8.13-7.83 (m, 1H), 7.42 (t, J = 8.4Hz, 1H), 6.83-6.77 (m, 2H), 4.88 (d, J = 3.1 Hz, 1H), 3.87- 3.78 (m,1H), 3.76-3.70 (m, 7H), 3.23 (s, 3H), 2.26 (s, 3H), 2.14 (br t, J = 7.1Hz, 2H), 1.46-1.39 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H), 1.18-1.11 (m, 2H),0.70 (t, J = 7.3 Hz, 3H). LCMS-ESI (pos.) m/z: 548.0 (M + H)⁺. 4.95-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one(Intermediate 3.0), cyclohexanesulfonamide (Enamine). Purification wasperformed by preparative HPLC: XSelect CSH Prep C18 10 um ODB 19 × 100mm, A: Water 0.1% formic acid B: ACN 0.1% formic acid, gradient.

N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy- 6-oxo-1,6-dihydro-5-pyrimidinyl)cyclohexanesulfonamide. ¹H NMR (600 MHz, DMSO-d₆) δ 7.46 (t,J = 8.49 Hz, 1 H) 6.85 (d, J = 8.56 Hz, 2 H) 3.79-3.73 (m, 6 H) 2.99 (brt, J = 3.15 Hz, 1 H) 2.19 (br d, J = 8.80 Hz, 4 H) 1.75 (br d, J = 10.82Hz, 2 H) 1.51-1.64 (m, 1 H) 1.38-1.48 (m, 2 H) 1.24-1.37 (m, 2H)1.07-1.20 (m, 5 H) 0.70 (t, J = 7.32 Hz, 3 H), 2 protons not observed.LCMS-ESI (pos.) m/z: 466.2 (M + H)⁺. 4.17 5-bromo-2-cyclopentyl-3-(2,6-dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one was prepared in ananalogous to the preparation of Intermediate 3.0 using cyclopentanecarbonitrile instead of pentanenitrile, 2-(5- fluoropyrimidin-2-yl)ethanesulfonamide (Intermediate 5.0). The purification was performedusing the method in Example 4.2.

N-[2-cyclopentyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. ¹H NMR (600 MHz, DMSO-d₆) δ11.49-11.69 (m, 1 H), 8.79-8.83 (m, 2 H), 8.44 (br s, 1 H), 7.43 (t, J =8.6 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 3.71- 3.74 (m, 7 H), 3.56-3.59(m, 2 H), 3.37-3.41 (m, 2 H), 1.74-1.81 (m, 2 H), 1.62-1.71 (m, 2 H),1.55-1.61 (m, 2 H), 1.36-1.45 (m, 2 H). LCMS-ESI (pos.) m/z: 520.2 (M +H)⁺. 4.24 5-bromo-3-(2,6- dimethoxyphenyl)-6-hydroxy-2-phenylpyrimidin-4(3H)-one was prepared in an analogous to thepreparation of Intermediate 3.0 using benzonitrile instead ofpentanenitrile, 2-(5- fluoropyrimidin-2- yl)ethanesulfonamide(Intermediate 5.0). The purification was performed using the method inExample 4.2.

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-phenyl-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2- yl)ethanesulfonamide. ¹HNMR (600 MHz, DMSO-d₆) δ 8.79-8.82 (m, 2 H), 8.32 (br s, 1 H), 7.09-7.21(m, 6 H), 6.49 (d, J = 8.7 Hz, 2 H), 3.68-3.76 (m, 2 H), 3.62 (s, 6 H),3.40-3.45 (m, 2 H). LCMS-ESI (pos.) m/z: 528.2 (M + H)⁺.

Following the procedure described in Example 4.0, the followingcompounds may be synthesized using the intermediates and conditionsdescribed in the following table (Table 2).

TABLE 2 Example Reagents Structure, Name and Data 4.105-bromo-2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxypyrimidin-4(3H)-one(Intermediate 3.0), (R)-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide and (S)-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide(Intermediate 5.6).

(R)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and(S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. 4.114,6-dimethoxypyrimdin-5-amine (CAS: 15846-15-8).

N-[2-butyl-1-(4,6-dimethoxypyrimidin-5-yl)-4-hydroxy-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.12 2-(pyridin-2-yl)ethane-1-sulfonamide (CAS: 776287-41-3).

N-[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-pyrimidin-5-yl]-2-(2- pyridyl)ethanesulfonamide. 4.132-(napthalen-2-yl)ethane-1- sulfonamide (CAS: 105908-38-1).

N-[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-pyrimidin-5-yl]-2-(2- naphthyl)ethanesulfonamide. 4.142-ethoxyacetonitrile (CAS: 62957- 60-2).

N-[1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-4-hydroxy-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.156-methoxypyridine-2-carbonitrile (CAS: 83621-01-6).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(6-methoxy-2-pyridyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.16Tetrahydrofuran-2-carbonitrile (CAS: 14631-43-7).

(S)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-tetrahydrofuran-2-yl-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-tetrahydrofuran-2-yl-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.18Tetrahydrofuran-3-carbonitrile (CAS: 14631-44-8).

(S)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-tetrahydrofuran-3-yl-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-tetrahydrofuran-3-yl-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.19 1-phenylethan-1-amine (CAS:618- 36-0).

(S)-N-[2-butyl-4-hydroxy-6-oxo-1-(1- phenylethyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-[2-butyl-4-hydroxy-6-oxo-1-(1- phenylethyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.20 1-phenylpropan-1-amine(CAS: 2941-20-0).

(S)-N-[2-butyl-4-hydroxy-6-oxo-1-(1- phenylpropyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-[2-butyl-4-hydroxy-6-oxo-1-(1- phenylpropyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.21 1-(oxan-4-yl)propan-1-amine(CAS: 854697-14-6).

(S)-N-[2-butyl-4-hydroxy-6-oxo-1-(1-tetrahydropyran-4-ylpropyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-[2-butyl-4-hydroxy-6-oxo-1-(1-tetrahydropyran-4-ylpropyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.22 Oxan-3-amine (CAS:120811-32- 7).

(S)- -(2-butyl-4-hydroxy-6-oxo-1-tetrahydropyran-3-yl-pyrimidin-5-yl)-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (R)-N-(2-butyl-4-hydroxy-6-oxo-1-tetrahydropyran-3-yl-pyrimidin-5-yl)-2-(5-fluoropyrimidin-2- yl)ethanesulfonamide. 4.232-methoxy-1-(oxan-4-yl)ethan-1- amine (CAS: 1340266-43-4).

(R)-N-[2-butyl-4-hydroxy-1-(2-methoxy-1-tetrahydropyran-4-yl-ethyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and(S)-N-[2-butyl-4-hydroxy-1-(2-methoxy-1-tetrahydropyran-4-yl-ethyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.255-methyl-2-furonitrile (CAS: 13714-86-8).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(5-methyl-2-furyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.26 1-methyl-1H-indazole-3-carbonitrile (CAS: 31748-44-4).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(1-methylindazol-3-yl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.27 (1S,2S)-1-Isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide (Intermediate 5.7).

(1S,2S)-N-(2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide. 4.285,5,5-Trifluoropentanonitrile (CAS: 89866-61-5).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-(4,4,4-trifluorobutyl)pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.29 4-hydroxybutanenitrile(CAS: 628- 22-8).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(3-hydroxypropyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.304-(Trifluoromethoxy)butyronitrile (CAS: 1301738-94-2).

N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-2-[3-(trifluoromethoxy)propyl]pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.31 2-methylpentanenitrile(CAS: 6339-13-5).

(R)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(1-methylbutyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide and (S)-N-[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(1-methylbutyl)-6-oxo-pyrimidin-5-yl]-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide. 4.32 Naphthalene-2-sulfonamide(CAS: 1576-47-2).

N-[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-pyrimidin-5-yl]naphthalene-2- sulfonamide.

Intermediate 5.0. Preparation of2-(5-fluoropyrimidin-2-yl)ethanesulfonamide

5-Fluoro-2-vinylpyrimidine, intermediate 5.0.1, To a solution of2-chloro-5-fluoropyrimidine (Sigma Aldrich, 10.0 g, 75.46 mmol) in DMF(100 mL) was added tributyl(vinyl)tin (31.1 g, 98.09 mmol) at RT. Thereaction mixture was pinged with N₂ for 5 min and Pd(PPh₃)₄ (2.62 g,2.26 mmol) was added. The reaction mixture was degassed with N₂ for 5min and stirred at 100° C. for 24 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to RT and quenchedwith water (100 mL). The aqueous layer was extracted with diethyl ether(2×100 mL). The combined organic layer was washed with brine (100 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive the product, which was purified by combi-flash chromatography(redisep column 120 g; elution: 6% EtOAc in hexane) to provideIntermediate 5.0.1 (8.0 g, 85.1%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ8.58-8.49 (m, 2H), 6.86 (dd, J=17.4, 10.6 Hz, 1H), 6.53 (d, J=17.3 Hz,1H), 5.70 (d, J=10.6 Hz, 1H). MS (ESI, positive ion) m/z: 125.1.

2-(5-Fluoropyrimidin-2-yl) ethanesulfonic acid, Intermediate 5.0.2, Asolution of Intermediate 5.0.1 (20.0 g, 16.12 mmol) in a saturatedaqueous solution of NaHSO₃ (80 mL) was stirred at RT for 12 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure to give the initial product whichwas purified by flash chromatography on (120 g Redisep elution: 4-10%H₂O in MeCN) to provide Intermediate 5.0.2 (16.0 g, 47.9%) as a whitesolid. ¹H NMR (400 MHz, DMSO) δ 8.89-8.73 (m, 2H), 3.17 (t, J=8.2 Hz,2H), 2.85 (t, J=8.2 Hz, 2H).

2-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)ethanesulfonamide,Intermediate 5.0.3, To a suspension of Intermediate 5.0.2 (16.0 g, 77.30mmol) in DCM (385 mL) was added oxalyl chloride (29.4 g, 231.8 mmol)followed by DMF (1 mL) at 0° C. The reaction mixture was stirred at RTfor 1 h and then concentrated under reduced pressure. The reactionmixture was azeotroped with cyclopentylmethylether to remove traces ofoxalyl chloride. The reaction mixture was diluted with DCM (385 mL),cooled to 0° C. and 4-methoxybenzylamine (31.8 g, 231.88 mmol) followedby TEA (39.1 g, 386.4 mmol) were added. The reaction mixture was stirredat RT for 12 h. After completion of the reaction (monitored by TLC), thereaction mixture was quenched with water (500 mL). The aqueous layer wasextracted with DCM (2×400 mL). The organic layer was washed with brine(1.0 L), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain the initial product which was purified by columnchromatography (silica, 100-200 mesh; elution 55% EtOAc in hexane) toprovide Intermediate 5.0.3 (13.5 g, 53.5%) as an off yellow solid. MS(ESI, positive ion) m/z: 326.1.

2-(5-Fluoropyrimidin-2-yl)ethanesulfonamide, Intermediate 5.0. To asuspension of Intermediate 5.0.3 (13.5 g, 41.41 mmol) in DCM (46 mL) wasadded TFA (207 mL) at 0° C. The reaction mixture was stirred at RT for12 h. After completion of the reaction (monitored by TLC), the reactionmixture was concentrated under reduced pressure to give the residuewhich was purified by flash chromatography (elution: 65% EtOAc inhexane) to provide Intermediate 5.0 (5.3 g, 62.5%) as an off yellowsolid. MS (ESI, positive ion) m/z: 206.0. ¹H NMR (400 MHz, DMSO) δ 8.77(s, 2H), 6.92 (s, 2H), 3.54-3.48 (m, 2H), 3.24-3.20 (s, 2H).

Intermediate 5.1. Preparation of(2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide

(E)-2-(But-2-en-2-yl)-5-fluoropyrimidine, Intermediate 5.1.1,2-Chloro-5-fluoro-pyrimidine (14.45 ml, 117 mmol), potassium(Z)-but-2-en-2-yltrifluoroborate (24.63 g, 152 mmol),tricyclohexylphosphine (6.56 g, 23.39 mmol), and Pd₂(dba)₃ (10.71 g,11.70 mmol) were added to a vial and then degassed and backfilled withnitrogen. To the vial, 1,4-dioxane (195 ml,) and aqueous potassiumphosphate tribasic (29.0 ml, 351 mmol) were added by syringe. Theresulting reaction was heated to 100° C. for 16 h. The reaction wascooled to RT. The organics were concentrated under reduced pressure. Theresidue was filtered through a plug of silica gel, then loaded ontosilica gel (0-20% EtOAc in hexanes) to afford Intermediate 5.1.1 (14.24g, 94 mmol, 80% yield). LCMS-ESI (POS.) M/Z: 153.1 (M+H)⁺.

2-(2-Chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-fluoropyrimidine,Intermediate 5.1.2, To a solution of pyrimidine-2-thiol (13.27 g, 118mmol) in DCM (329 ml) was added sulfuryl dichloride (9.62 ml, 118 mmol).The reaction was stirred at 0° C. for 1 h and a further 1 h at 23° C. Tothe cloudy reaction was added Intermediate 5.1.1 (15 g, 99 mmol)dropwise. The reaction was further stirred for 1 h. The reaction mixturewas then concentrated in vacuo. A saturated aqueous solution of sodiumbicarbonate was added to the mixture to neutralize the reaction mixture.The reaction was extracted with EtOAc and concentrated in vacuo. Theresidue was purified on silica gel with 0-25% EtOAc in hexanes to givethe desired product Intermediate 5.1.2 (21 g, 70.3 mmol 71.3% yield).LCMS-ESI (POS.) M/Z: 291.1 (M+H)⁺.

2-(2-Chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-fluoropyrimidine,Intermediate 5.1.3, To a solution of Intermediate 5.1.2 (21 g, 70.3mmol) in DCM (201 mL) was added 3-chlorobenzoperoxoic acid (24.26 g, 141mmol) at 0° C. The reaction was stirred at 23° C. for 1 day. Thereaction was concentrated in vacuo and an aqueous solution of sodiumbicarbonate and sodium thiosulfate was added. The mixture was extractedwith EtOAc and concentrated in vacuo and purified on silica gel elutingwith 0-100% EtOAc in hexane to give the desired product Intermediate5.1.3 (18 g, 54.4 mmol 77% yield). LCMS-ESI (POS.) M/Z: 331.1 (M+H)⁺.

(E)-3-(5-Fluoropyrimidin-2-yl)but-2-ene-2-sulfonamide, Intermediate5.1.4, To a stirred solution of Intermediate 5.1.3 (18 g, 54.4 mmol) inMeOH (136 ml) was added potassium carbonate (15.04 g, 109 mmol). Thereaction was stirred at 23° C. for 16 h and was then concentrated invacuo. The sulfinate was dissolved in water (231 mL, 46.3 mmol) andpotassium acetate (4.54 g, 46.3 mmol) was added, followed by(aminooxy)sulfonic acid (10.47 g, 93 mmol). The reaction was stirred at23° C. for 3 h and was then extracted with EtOAc and concentrated invacuo. The product was purified on silica gel eluting with 0-80% EtOAcin hexanes to give the desired product Intermediate 5.1.4 (11.77 g, 46.3mmol). LCMS-ESI (POS.) M/Z: 232.1 (M+H)⁺.

(2S,3R)-3-(5-Fluoropyrimidin-2-yl)butane-2-sulfonamide, Intermediate5.1. To a solution of Intermediate 5.1.4 (0.77 g, 3.33 mmol) in EtOH(8.32 ml) was added zinc(II) trifluoromethanesulfonate (0.121 g, 0.333mmol), and(R)-(−)-4,12-Bis(diphenylphosphino)[2.2]paracyclophane(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate, min. 97% (Strem chemicals, 45-0217, 0.116 g, 0.133mmol). The reaction mixture was placed under an atmosphere of hydrogen.The reaction was stirred for 16 h and was then filtered, concentrated invacuo, and purified on silica gel eluting with 0-80% EtOAc in hexanes togive the desired product. The combined product was recrystallized fromEtOH to give the desired product (0.46 g, 60%, 99% ee) Intermediate 5.1.LCMS-ESI (POS.) M/Z: 234.2 (M+H)⁺.

Intermediate 5.2.5. Preparation of(R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide and(S)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

5-Fluoro-2-(prop-1-en-2-yl)pyrimidine, Intermediate 5.2.1, A mixture of2-chloro-5-fluoropyrimidine (50.0 g, 377.0 mmol. CAS: 62802-42-0),potassium trifluoro(prop-1-en-2-yl)borate (84.0 g, 566.0 mmol) and K₂CO₃(78.0 g, 566.0 mmol) in 1,4-dioxane (400 mL) and water (100 mL) wereadded to a sealed tube (1 L). The reaction mixture was degassed andpurged with nitrogen for 20 min. PdCl₂(dppf) (7.70 g, 9.43 mmol) wasadded and the reaction tube was sealed and heated to 70° C. After 18 h,the reaction mixture was cooled to RT, diluted with diethyl ether (500mL), and filtered through Celite® filter aid. The filter cake was washedwith diethyl ether (500 mL). The combined filtrate was extracted withdiethyl ether (2×2 L). The organic layer was washed with cold water (2×2L), dried over Na₂SO₄ and concentrated under reduced pressure at 35° C.The material was purified by column chromatography over silica gel(60-120 mesh) using 5% EtOAc in hexanes as an eluent to giveIntermediate 5.2.1 (41.0 g, 297.0 mmol, 79% yield) as a colourless oil.¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 2H), 6.38 (t, J=1.2 Hz, 1H), 5.54 (t,T=1.2 Hz, 1H), 2.26 (dd, J=1.2, 0.8 Hz, 3H).

2-(2-Chloro-1-(pyrimidin-2-ylthio)propan-2-yl)-5-fluoropyrimidine,Intermediate 5.2.2, To a stirred solution of pyrimidine-2-thiol (49.9 g,356.0 mmol, CAS: 1450-85-7) in DCM (750 mL) was added sulfuryl chloride(36.2 mL, 356.0 mmol) slowly at 0° C. The reaction mixture was stirredat 0° C. for 2 h followed by stirring at RT for 2 h. A solution ofIntermediate 5.2.1 (41.0 g, 297.0 mmol) in DCM (410 mL) was added slowlyto the reaction mixture and stirred at RT for 16 h. The reaction mixturewas quenched with saturated aqueous NaHCO₃ solution (1 L) and extractedwith DCM (2×1.0 L). The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel (60-120 mesh) using 1%to 15% EtOAc in hexanes as an eluent to give Intermediate 5.2.2 (37.5 g,44% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 2H), 8.54 (d, J=4.8 Hz,2H), 7.00 (t, J=4.8 Hz, 1H), 4.48 (d, J=13.6 Hz, 1H), 4.39 (d, J=13.6Hz, 1H), 2.16 (s, 3H).

2-(2-Chloro-1-(pyrimidin-2-ylsulfonyl)propan-2-yl)-5-fluoropyrimidine,Intermediate 5.2.3, To a stirred solution of Intermediate 5.2.2 (75.0 g,263.0 mmol) in DCM (750 mL) was added mCPBA (114.0 g, 658.0 mmol) underN₂ atmosphere, and the mixture was stirred at RT for 16 h. The reactionmixture was quenched with water (1 L) and extracted with DCM (4×1 L).The organic layer was washed with saturated aqueous NaHCO₃ solution (4×2L) followed by brine solution (2 L), dried over anhy. Na₂SO₄, filteredand concentrated under reduced pressure. The solid residue wastriturated with diethyl ether (1 L), filtered and dried under vacuum togive Intermediate 5.2.3 (55 g, 66% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.98(d, J=4.8 Hz, 2H), 8.56 (s, 2H), 7.59 (t, J=4.8 Hz, 1H), 5.17 (d, T=14.6Hz, 1H), 4.72 (dd, J=14.6 Hz, 1H), 2.30 (s, 3H). LCMS-ESI (pos.) m/z:317.0 (M+H)⁺.

2-(5-Fluoropyrimidin-2-yl)prop-1-ene-1-sulfonamide, Intermediate 5.2.4,To a stirred solution of Intermediate 5.2.3 (50.0 g, 158.0 mmol) in MeOH(500.0 mL) was added potassium carbonate (43.6 g, 316 mmol). The mixturewas then stirred at RT for 16 h. The reaction was concentrated underreduced pressure. The solid was triturated with diethyl ether (1 L),filtered and dried under vacuum. The solid was added to water (350 mL)followed by addition of potassium acetate (28.6 g, 291.0 mmol) and(aminooxy)sulfonic acid (65.9 g, 583.0 mmol) in portions at 0° C. Afterthe addition was complete, the reaction mixture was warmed to RT andstirred for 2 h. The reaction mixture was extracted with 10% MeOH inEtOAc (2×500 mL). The organic layer was washed with brine (250.0 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The material was absorbed onto a plug of silica gel andpurified by flash chromatography through a Redi-Sep pre-packed silicagel column (80.0 g), eluting with a gradient of 0% to 50% EtOAc inhexanes, to give Intermediate 5.2.4 (22.0 g, 64% yield). ¹H NMR (400MHz, CDCl₃) δ 8.64 (d, J=5.0 Hz, 2H), 7.81 (s, 1H), 4.93 (s, 2H), 2.611(s, 3H). LCMS-ESI (POS.) m/z: 218.0 (M+H)⁺.

(R)-2-(5-Fluoropyrimidin-2-yl)propane-1-sulfonamide and(S)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Intermediate 5.2.5,To a solution of Intermediate 5.2.4 (22.0 g, 101.0 mmol) in MeOH (225.0mL) was added zinc trifluoromethanesulfonate (9.20 g, 25.3 mmol),bis(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (1.028 g, 2.53 mmol)and Josiphos-1 (1.62 g, 2.53 mmol). The reaction mixture was degassedand purged with argon for 10 min. The reaction vessel was purged withhydrogen and kept under hydrogen pressure (3-4 bar) in an autoclave (450mL) at 80° C. for 48 h. The reaction mixture was concentrated underreduced pressure. The residue was absorbed onto a plug of silica gel(60-120 mesh) and purified by flash chromatography through a Redi-Seppre-packed silica gel column (80.0 g), eluting with a gradient of 0% to50% EtOAc in hexanes to give Intermediate 5.2.5,

Intermediate 5.2. Preparation of(R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or(N)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

(R)-2-(5-Fluoropyrimidin-2-yl)propane-1-sulfonamide or(S)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Intermediate 5.2.Intermediate 5.2.5 was separated using chiral SFC (YMC Amylose SA(250×4.6 mm, 5 μm column), 70:30 liquid CO₂ and MeOH, 3 mL/min, 100 bar)to give Intermediate 5.2 (99.6% ee). ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s,2H), 4.77 (s, 2H), 3.94 (dd, J=14.1, 8.8 Hz, 1H), 3.85-3.75 (m, 1H),3.41 (dd, J=14.1, 4.3 Hz, 1H), 1.50 (d, J=6.9 Hz, 3H). LCMS-ESI (pos.)m/z: 220.1 (M+H)⁺.

Intermediate 5.3. Preparation of(R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or(S)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

(R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or(S)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Intermediate 5.3.Further purification under the conditions described in Intermediate 5.2delivered Intermediate 5.3 (98.8% ee). ¹H NMR (400 MHz, CDCl₃) δ 8.58(s, 2H), 4.77 (s, 2H), 3.94 (dd, J=14.1, 8.8 Hz, 1H), 3.85-3.75 (m, 1H),3.41 (dd, J=14.1, 4.3 Hz, 1H), 1.50 (d, J=6.9 Hz, 3H). LCMS-ESI (pos.)m/z: 220.1 (M+H)⁺.

Intermediate 5.4. Preparation of(S)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide or(R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide

(S)-1-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide or(R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Intermediate5.4. To a solution of piperidine-3-sulfonamide hydrochloride (1.00 g,4.98 mmol) in DMSO (24.9 mL) was added 2-chloro-5-fluoropyrimidine (3.30g, 24.9 mmol) followed by Hunig's base (8.67 mL, 49.8 mmol). The flaskwas fitted with a condenser and placed into a reaction block preheatedto 100° C. After 2 h, the mixture was cooled to RT and was diluted withDCM and water and the layers were separated. The organic layer waswashed with water (×3) and brine (×2). The combined organic layers werewashed with brine (×1), dried with magnesium sulfate, filtered andconcentrated under reduced pressure. The solids were triturated with IPAand the solid was purified by chiral separation method (SFC: 100×4.6 mmAD-H column with 25% MeOH (20 mM NH₃), 5 mL/min) to give Intermediate5.4. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (2H, d, J=0.83 Hz) 6.93 (2H, s)4.94-5.06 (1H, m) 4.56 (1H, br d, J=12.23 Hz) 2.88-3.00 (2H, m) 2.81(1H, td, J=12.83, 2.75 Hz) 2.18 (1H, br d, J=12.75 Hz) 1.76-1.85 (1H, m)1.63-1.75 (1H, m) 1.38-1.52 (1H, m).

Intermediate 5.5. Preparation of(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine, Intermediate 5.5.1, To a 500mL round bottomed flask was added 2-chloro-5-methylpyrimidine (12 g, 93mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was pingedwith N₂ (5×), then 1,4-dioxane (200 ml), and water (20.00 ml) wereadded. The resulting yellow suspension was bubbled with Ar for 15 minand then 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride(Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) wasadded. A reflux condenser was attached and the reaction was warmed to90° C. in an oil bath and stirred under N₂ for 16.5 h. The reaction wasthen cooled to RT. The reaction was diluted with water (250 mL), andextracted with EtOAc (2×250 mL). The organic layers were combined, dried(MgSO₄), and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with 0-20% EtOAc/hexanes) to affordIntermediate 5.5.1 (12.96 g, 97 mmol, 100% yield) as a yellow/orangeoily solid. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 2H), 7.01-7.20 (m, 1H),6.57 (dd, J=15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J=6.8, 1.6 Hz,1H). MS (ESI pos. ion) m/z: 135.2 (M+H).

(1R,2R)-1-(5-Methylpyrimidin-2-yl)propane-1,2-diol, Intermediate 5.5.2,Racemic conditions: To a solution of(E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine (Intermediate 5.5.1, 5.75 g,42.9 mmol) and 4-methylmorpholine-4-oxide (7.53 g, 64.3 mmol) in acetone(60 mL) and water (6 mL) was added osmium tetroxide, 4 wt. %, in water(0.681 mL, 0.111 mmol). The reaction was stirred at RT under N₂ 21.5 h.LCMS showed complete conversion to a product corresponding to the massof the desired product (M+H=169). The reaction was passed through aVarian Chem-Elut cartridge to remove water and then concentrated invacuo. Water was still present. The residue was dissolved in DCM, dried(MgSO₄), and concentrated. The residue was purified by flashchromatography (120 g SiO₂, 0-10% MeOH/DCM) to give the racemic syn-diol(1R,S),(2R,S)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (5.85 g, 34.8mmol, 81% yield) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.59(s, 2H), 4.67 (br. s., 1H), 4.33 (br. s., 1H), 4.09-4.25 (m, 1H), 2.86(d, J=7.2 Hz, 1H), 2.36 (s, 3H), 1.30 (d, J=6.6 Hz, 3H). MS (ESI pos.ion) m/z: 169.2 (M+H).

Chiral conditions: Prepared a batch of AD-mix-beta from: (26 mg, 0.07mmol) K₂OsO₂(OH)₄; (16.4 g, 49.9 mmol) K₃Fe(CN)₆; (6.89 g, 49.9 mmol)K₂CO₃; (125 mg, 0.16 mmol) (DHQD)₂PHAL. In a 50 mL round bottom flaskwas added t-BuOH (5 mL), water (5.00 mL), and 1.4 g of AD-mix-beta(prepared above) and methanesulfonamide (95 mg, 1.000 mmol). The mixturewas stirred at RT until clear and then cooled to 0° C.(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine (Intermediate 5.5.1, 168 mg, 1mmol) in t-BuOH (1 mL) was added and the slurry was stirred at 0° C. 2h. LCMS (1.5 h) shows 10% conversion. The reaction was warmed slowly toRT as the ice bath melted and stirred an additional 22 h. LCMS showed90% conversion. The reaction was quenched with saturated aqueous sodiumsulfite (10 mL) and extracted with EtOAc (2×20 mL). The combined organiclayers were washed with 2 N NaOH (10 mL), dried (MgSO₄), andconcentrated. The isolated product was only 60 mg of clear oil. LCMS ofthe aqueous layer showed a large peak corresponding to the desired diolremained in the aqueous layer. The aqueous layer was extracted with DCM(2×50 mL), EtOAc (2×50 mL), and 10% IPA in CHCl₃ (2×50 mL). The aqueouslayer still showed presence of diol. The combined organic layers wereconcentrated and the residue purified by flash column chromatography (12g SiO₂, 5-100% 3:1 EtOAc:EtOH/heptane) to give Intermediate 5.5.2 (88.6mg, 0.527 mmol, 52.7% yield) as a clear, colorless oil. Chiral Analysis:SFC Chiral Analysis shows the % ee to be 94.8% using a AS-H (100×2.1 mm,3 um), 10% organic modifier (iPrOH with 20 mM ammonia), 90% carbondioxide. F=1.0 mL/min, column temp=RT, BRP=105 bar,

5-Methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine, intermediate 5.5.3,To a solution of Intermediate 5.5.2 (1.46 g, 8.68 mmol) in DCM (25 mL)(cooled with a RT water bath) was added 1,1,1-trimethoxyethane (2.50 mL,2.29 mmol), then chlorotrimethylsilane (2.50 mL, 19.7 mmol) was added in2 portions 5 min apart. The reaction had a small exotherm on the firstportion of addition of TMSCl (23-28° C.). The reaction was stirred at RTunder N₂ 23 h. LCMS indicated incomplete conversion. An additional 1.25equiv. of 1,1,1-trimethoxy ethane (1.25 mL, 9.95 mmol) andchlorotrimethylsilane (1.25 mL, 9.85 mmol) were added, and the reactionwas stirred an additional 24 h. LCMS (24 h) showed 75% conversion tochloroacetate (M+H=229). The reaction was concentrated in vacuo. Theresidue was dissolved in MeOH (20 mL) and potassium carbonate (1.500 g,10.85 mmol) was added. The reaction was then stirred at RT for 4 h. LCMS(4 h) showed complete conversion to product corresponding to the desiredepoxide (M+H=151) with some residual orthoacetate (M-OMe+H2O=211) withthe same retention time as the product. The reaction was filtered, thefilter cake washed with DCM (5 mL), and the combined filtratesconcentrated in vacuo. The reaction product was purified by flash columnchromatography on silica gel eluting with 0-100% EtOAc/hexanes) toafford Intermediate 5.5.3 (1.00 g, 6.6 mmol, 77%) as a clear, lightyellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 2H), 3.81 (d, J=1.9 Hz,1H), 3.32-3.53 (m, 1H), 2.31 (s, 3H), 1.50 (d, J=5.1 Hz, 3H). MS (LSIpos. ion) m/z: 151.2 (M+H).

(1R,2S)-2-(Benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol,Intermediate 5.5.4, To a solution of Intermediate 5.5.3 (250 mg, 1.332mmol) in DCM (5 mL) was added benzo[d]thiazole-2-thiol (245 mg, 1.465mmol), followed by tris(((trifluoromethyl)sulfonyl)oxy)ytterbium (83 mg,0.133 mmol). The suspension was heated in a 35° C. heating block 17 h,after 10 min, the reaction became a clear, colorless solution. LCMS (1h) showed 80% conversion to a peak corresponding to the mass of desiredproduct (M+H=318). LCMS (17 h) showed 100% conversion to desiredproduct. The reaction was cooled to RT and then loaded on a plug ofsilica and purified by flash chromatography (12 g SiO₂, 5-100% 3:1EtOAc:EtOH/heptane) to afford Intermediate 5.5.4 (428 mg, 1.348 mmol,101% yield) as a clear, colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 8.60(s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.71-7.81 (m, 1H), 7.42 (td, J=7.7, 1.3Hz, 1H), 7.27-7.35 (m, 1H), 5.31 (s, 1H), 4.70 (qd, J=7.1, 3.1 Hz, 1H),2.32 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). MS (ESI pos. ion) m/z: 318.2(M+H).

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole,Intermediate 5.5.5, To a 50 mL flask equipped with a magnetic stirrerwas charged a solution of racemic Intermediate 5.5.4 (350 mg, 1.103mmol) in 2-MeTHF (1.1 mL). The reaction mixture was cooled to −78° C.and potassium bis(trimethylsilyl)amide, (1M solution in THF, 1.32 μL,1.32 mmol) was added dropwise (total addition time: 2 min, turned to ayellow solution). The resulting mixture was stirred for 1 h and thenmethyl trifluoromethanesulfonate (374 μl, 3.31 mmol) was added dropwise(turned a lighter yellow solution). The reaction mixture was stirred at−78° C. for 15 min. LCMS showed complete conversion of starting materialto the product. The reaction mixture was quenched with saturated aqueousNH₄Cl solution (30 mL) at −78° C. The reaction was then warmed to RT andthe aqueous layer was back extracted with EtOAc (3×75 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), and concentrated.The material obtained was purified by chromatography through a Biotage50 g ultra silica gel column, eluting with a gradient of 0% to 25% EtOAcin hexane, to provide Intermediate 5.5.5 (0.32 g, 75%) as a light-yellowoil.

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole,Intermediate 5.5.6. A solution of Intermediate 5.5.5 (313 mg, 0.944mmol) in DCM (2.8 mL) at 0° C. was treated with 3-chloroperoxybenzoicacid, (77% max, 476 mg, 2.125 mmol). The reaction was stirred at 0° C.for 1 h before the ice bath was removed. LCMS showed desired product,sulfoxide, and the presumed sulfoxide/sulfone. The mixture was allowedto warm to RT and was stirred for an additional 40 h. The reaction wasquenched with saturated aqueous sodium bisulfite (6 mL), followed byaddition of saturated aqueous sodium bicarbonate (5 mL) and theresulting mixture was stirred for 10 min. The reaction was extractedwith EtOAc (2×20 mL) and the organic layers combined, washed withsaturated aqueous NaHCO₃ (10 mL), brine (10 mL), dried (MgSO₄) andfiltered. Iodide/starch strip indicator shows no peroxide present. Thefiltrates were concentrated to give a clear, colorless oil (360 mg).Purification of the residue by flash chromatography (40 g SiO₂, 0-100%3:1 EtOAc:EtOH/heptane) gave Intermediate 5.5.6 (285 mg, 0.784 mmol, 83%yield, 77% purity) as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 8.57 (s,2H), 8.18-8.28 (m, 1H) 7.97-8.05 (m, 1H), 7.54-7.67 (m, 2H), 5.25-5.34(m, 1H), 4.23 (qd, J=7.2, 3.1 Hz, 1H), 3.41 (s, 3H), 2.31 (s, 3H), 1.49(d, J=1.2 Hz, 3H). MS (ESI pos. ion) m/z: 364.0 (M+H).

Potassium(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfinate,Intermediate 5.5.7, To a solution of racemic Intermediate 5.5.6 (268 mg,0.74 mmol) in MeOH (1.84 mL) was added potassium carbonate (204 mg, 1.48mmol). The reaction was stirred at RT for 17 h. LCMS showed desiredIntermediate 5.5.7, The reaction was concentrated in vacuo (yellowsolid) and used directly in the following step. Epimerization occurredin this reaction (15%).

(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Intermediate 5.5. To a suspension of Intermediate 5.5.7 (198 mg, 0.738mmol) in water (3.7 mL) was added potassium acetate (72.4 mg, 0.738mmol), followed by hydroxylamine-o-sulfonic acid, 97% (167 mg, 1.476mmol). The reaction mixture was stirred at RT for 4.5 h. LCMS showeddesired product formation plus a small peak that corresponded to thestereoisomer. The reaction mixture was extracted with EtOAc (2×) and theorganics were combined, dried (Na₂SO₄), and concentrated. The residuewas loaded onto a silica gel column eluting with 0-30% (3:1EtOAc:EtOH)/DCM to afford Intermediate 5.5 (114 mg, 0.465 mmol, 63.0%yield) as a white solid, (contained 15% other diastereomer). ¹H NMR (300MHz, CDCl₃) δ 8.63 (s, 2H), 5.10 (d, J=3.3 Hz, 1H), 4.78 (br. s., 2H),3.74 (qd, J=7.1, 3.3 Hz, 1H), 3.51 (s, 3H), 2.36 (s, 3H), 1.33 (d, J=7.1Hz, 3H). MS (ESI pos. ion) m/z: 246.1 (M+H).

Intermediate 5.6. Preparation of(R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide and(S)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Fluoro-2-(prop-1-en-1-yl)pyrimidine and(Z)-5-fluoro-2-(prop-1-en-1-yl)pyrimidine, Intermediate 5.6.1, Tomagnesium turnings (9.0 g, 371.9 mmol) was added 1-2 crystals of iodineunder anhydrous conditions. The mixture was heated at 60° C. for 5 minunder reduced pressure to activate the magnesium. The flask was thencooled to RT and THF (370 mL) was added. The resulting mixture washeated to 65° C., (Z/E)-1-bromo-1-propene (45 g, 371.9 mmol) was addeddropwise, and the mixture was then stirred at 65° C. for 2 h undernitrogen atmosphere. Thereafter, the mixture was cooled to RT andtransferred to an ice bath. Zinc chloride (1M in diethyl ether, 283 mL,283 mmol) was then added dropwise over 10 min (The internal temperatureof the reaction was kept 10° C.-15° C. dining the addition) and theresulting organozinc reagent was stirred at RT for 45 min. In a separateround bottom flask, a solution of 2-chloro-5-fluoropyrimidine(commercially available from Novochemy, Jupiter, Fla., USA) (25 g, 189mmol), S-phos (7.7 g, 18.8 mmol) and palladium (II) acetate (2.1 g, 9.4mmol) in THF (38 mL) was degassed with nitrogen gas for 5 min. Theorganozinc reagent was then added dropwise. The resulting mixture washeated at 60° C. for 12 h. After completion of reaction (monitored byTLC), the reaction mixture was quenched with water (50 mL) and acidifiedwith 1N hydrochloric acid (700 mL) pH 2. The mixture was then extractedwith diethyl ether (2×500 mL). The combined organic layers were washedwith brine (200 mL), dried over sodium sulphate and concentrated underreduced pressure at 20° C. to a volume of approximately 50 mL, which wasused as in the next step without further purification.

(S)-1-(5-Fluoropyrimidin-2-yl)propane-2-sulfonic acid and(R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonic acid, Intermediate5.6.2, To a solution of Intermediate 5.6.1 (188.6 mmol) in THF (ca. 50mL) was added an aqueous solution of sodium bisulfite (19.6 g, 188.6mmol in 100 mL of H₂O). The reaction mixture was stirred at RT for 20 h.Once the reaction was complete (monitored by TLC), the mixture wasacidified to approximately pH1 with concentrated HCl (10 mL). Theaqueous layer was then concentrated under reduced pressure to furnishthe product which was suspended in EtOH (250 mL). The product was heatedto reflux, filtered hot and rinsed with hot EtOH (100 mL). The filtratewas concentrated under reduced pressure to give a brown solid which wasrecrystallized from IPA (50 mL) to afford Intermediate 5.6.2 (20 g, 48%)as a brown solid. ¹H NMR (400 MHz, D₂O) δ 8.69 (s, 2H), 3.47 (td, J=9.8,8.2, 4.0 Hz, 2H), 3.06 (dd, J=16.1, 10.2 Hz, 1H), 1.24 (d, J=6.5 Hz,3H). MS-ESI (neg.) m/z: 118.9 (M−H)⁻.

(R)-1-(5-Fluoropyrimidin-2-yl)propane-2-sulfonamide and(S)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Intermediate 5.6. Asolution of Intermediate 5.6.2 (80 g, 360 mmol) in thionyl chloride (268mL, 3600 mmol) was heated at 60° C. for 3 h. The reaction wasconcentrated under reduced pressure to afford the sulfonyl chloride,which was azeotroped with toluene (3×300 mL). The residue was dilutedwith DCM (1.0 L) and ammonia gas was bubbled through for 15 min at −78°C. The mixture was then stirred at RT for 1 h. Thereafter, the reactionmixture was filtered through a pad of Celite filter aid and the pad waswashed with DCM (100 mL) and EtOAc (100 mL). The combined filtrate wasthen concentrated under reduced pressure to obtain the material, whichwas purified by column chromatography (silica; 100-200, elution 0-60%EtOAc in hexane) to give Intermediate 5.6 (43 g, 54%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=1.1 Hz, 2H), 6.90 (s, 2H),3.57-3.51 (m, 2H), 2.93 (dd, J=15.4, 11.1 Hz, 1H), 1.19 (d, J=6.5 Hz,3H). MS-ESI (pos.) m/z: 220.0 (M+H)⁺.

Intermediate 5.7. Preparation of(1S,2S)-1-(5-fluoropyrimidin-2-yl)-1-isopropoxypropane-2-sulfonamide

5-Methylpyrimidine-2-carbonitrile, Intermediate 5.7.1. A solution of2-chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5.0 L)was degassed with N₂ for 20 min and dppf (108 g, 194 mmol, 0.05 equiv)and Pd₂(dba)₃ (178 g, 194 mmol, 0.05 equiv) were added to the reactionmixture. Zn(CN)₂ (685 g, 5834 mmol, 1.5 equiv) was added, and thereaction mixture was heated at 100° C. for 16 h. The reaction wasquenched with water (5.0 L) and stirred for 10 min. The reaction mixturewas then filtered through a pad of Celite brand filter agent. Thefiltrate was diluted with water (4.0 L) and extracted with EtOAc (2×4.0L). The combined organic layers were washed with brine (4 L), dried overNa₂SO₄. filtered, and concentrated under reduced pressure to give theproduct which was further purified by column chromatography using silicagel (60-120 mesh) and 0-10% EtOAc in hexanes to obtain Intermediate5.7.1 (330 g, 71%) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89(s, 2H), 2.39 (s, 3H).

N,N-Bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide,Intermediate 5.7.2, To a solution of Intermediate 5.8 (293 g, 839 mmol,2.0 equiv) in THF (2.0 L) was added isopropylmagnesium chloride (420 mL,839 mmol, 2.0 equiv, 2.0 M in diethyl ether) at 0° C. The reactionmixture was stirred at 25° C. for 3 h. To the reaction mixture was added5-methylpyrimidine-2-carbonitrile (50 g, 420 mmol, 1.0 equiv) in THF(100 mL) at 0° C. The resulting mixture was then stirred at RT for 2 h.The reaction was quenched with 1.5 N HCl (500 mL), and water (2.0 L) wasadded. The resulting mixture was then stirred for 10 min. The mixturewas extracted with EtOAc (2×1 L) and the combined organic layers werewashed with brine (500 mL), dried over Na₂SO₄ and filtered. The organiclayer was concentrated under reduced pressure to provide the compoundwhich was purified by column chromatography using silica gel (100-200mesh) and 0-50% EtOAc in hexanes as eluent to obtain Intermediate 5.7.2(60 g, 30% yield) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90(s, 2H), 7.15-7.09 (m, 4H), 6.85-6.80 (m, 4H), 4.34-4.18 (m, 5H), 3.71(app s, 6H), 2.39 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). MS (ESI+ve ion) m/z:(M+H)⁺: 470.0.

(E)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)prop-1-ene-2-sulfonamide,Intermediate 5.7.3, To a solution of Intermediate 5.7.2 (120 g, 256mmol, 1.0 equiv) in DMF (1.2 L) was added 2-iodopropane (129 mL, 1278mmol, 5.0 equiv) and potassium carbonate (70.6 g, 511 mmol, 2.0 equiv).The reaction mixture was then stirred at 60° C. for 14 h. The reactionwas quenched with water (1.0 L), stirred for 10 min, and extracted withEtOAc (2×1 L). The combined organic layers were washed with brine (1 L),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the material. The product thus obtained was purified by columnchromatography using silica gel (100-200 mesh) and 0-50% EtOAc inhexanes as eluent to obtain Intermediate 5.7.3 (75 g, 57.4% yield) as anoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 2H), 7.09 (d,J=8.3 Hz, 4H), 6.86 (d, J=8.3 Hz, 4H), 4.16 (s, 4H), 3.73 (s, 3H), 3.73(s, 3H), 3.71-3.67 (m, 1H), 2.31 (s, 3H), 1.87 (s, 3H), 1.19-1.16 (m,6H). MS (ESI+ve ion) m/z: (M+H)⁺: 512.1.

(1S,2R)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Intermediate 5.7.4, To a solution of Intermediate 5.7.3 (180 g, 352mmol, 1.0 equiv) in MeOH (1.8 L) was added zinc triflate (256 g, 704mmol, 2.0 equiv) and (S)—RuCl[(p-cymene(BINAP)]Cl (6.54 g, 7.04 mmol,0.02 equiv). The resulting mixture was then heated at 60° C. under H₂pressure (60 psi) for 16 h. The reaction mixture was concentrated underreduced pressure to obtain an initial product which was further purifiedby column chromatography using silica gel (60-120 mesh) and 0-50% EtOAcin DCM as eluent to obtain Intermediate 5.7.4 (140 g, 77%, 92% ee) as anoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 2H), 7.25-7.15 (m,4H), 6.95-6.75 (m, 4H), 4.82 (dd, J=7.8, 1.8 Hz, 1H), 4.39 (d, J=15.6Hz, 2H), 4.13 (d, J=15.7 Hz, 2H), 3.82 (qd, J=8.5, 7.9, 6.0 Hz, 1H),3.65 (app s, 6H), 3.41-3.35 (m, 1H), 2.27 (s, 3H), 1.12 (dd, J=6.2, 1.8Hz, 3H), 1.02 (dd, J=7.1, 2.0 Hz, 3H), 0.96 (dd, J=6.3, 1.8 Hz, 3H). MS(ESI+ve ion) m/z: (M+H)⁺: 514.2.

(1S,2S)-1-Isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Intermediate 5.7. To a solution of Intermediate 5.7.4 (140.0 g, 273mmol, 1.0 equiv) in DCM (500 mL) was added TFA (250 mL) at 0° C. Theresulting reaction mixture was then stirred at RT for 16 h. Next, thereaction mixture was concentrated under reduced pressure, dissolved inDCM (1.0 L) and washed with a saturated aqueous NaHCO₃ solution (1.0 L).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain the initial material which was furtherpurified by column chromatography using silica gel (60-120 mesh) and0-2% MeOH in DCM to obtain Intermediate 5.7 (72 g, 97% yield, 90% ee) asan off white solid. Intermediate 5.7 (72 g, 90% ee) was suspended in IPA(500 mL) and heated to 70° C. until the mixture became homogeneous. Oncethe solution became homogeneous, the mixture was cooled to RT overnight.The white solid thus obtained was filtered, dried under vacuum to obtainIntermediate 5.7 (30 g, >99%). The mother liquor was concentrated, andthe solid obtained was recrystallized again utilizing the sameprocedure. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, J=2.3 Hz, 2H), 6.45 (d,J=2.4 Hz, 2H), 4.68 (dd, J=8.8, 2.5 Hz, 1H), 3.59-3.52 (m, 1H), 3.48(ddd, J=9.7, 7.4, 4.9 Hz, 1H), 2.29 (d, J=2.6 Hz, 3H), 1.13 (dd, J=6.1,2.5 Hz, 3H), 0.93 (dd, J=7.1, 2.5 Hz, 3H), 0.88 (dd, J=6.3, 2.5 Hz, 3H).MS (ESI+ve ion) m/z: (M+H)⁺: 274.1.

Intermediate 5.8: Preparation ofN,N-bis(4-methoxybenzyl)ethanesulfonamide

Bis(4-methoxybenzyl)amine, Intermediate 5.8.1. 4-Methoxybenzylamine(neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37mol, 1 eq) were added to a 10 L round bottomed flask at RT withstirring. The reaction spontaneously warmed and a white precipitate wasobserved. The mixture was stirred for 1 h. To the above mixture wasadded anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30min. This was followed by the addition of sodium borohydride granules(99 g, 2.62 mol, 0.6 eq) portionwise over 2 h. During the addition ofNaBH₄, the internal temperature of the reaction rose to 42° C. Theresulting mixture was then stirred at RT overnight. Next, the reactionwas quenched slowly with water (600 mL). The mixture was thenconcentrated on a rotary evaporator at 50° C. The residue waspartitioned between water (4 L) and DCM (4 L). The aqueous layer wasextracted with more DCM (2×2 L). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo to give Intermediate5.8.1 (1112 g, 99% yield) as a semi-solid. The material was useddirectly in the next step without further purification. ¹H-NMR (400 MHz,CDCl₃) δ 7.28 (t, J=7.12 Hz, 4H), 6.89 (d, J=8.60 Hz, 4H), 3.83 (app s,6H), 3.76 (s, 4H) (—NH proton not observed). MS (ESI pos. ion) m/z:=258.4 (M+H)⁺.

N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Intermediate 5.8. To asolution of bis(4-methoxybenzyl)amine Intermediate 5.8.1 (900 g, 3.49mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq),followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19mol, 1.2 eq). The internal temperature was kept between 5-10° C. duringthe addition of the ethane sulfonyl chloride. Once the addition wascomplete, the cooling bath was removed. After 1.5 h, TLC showed completeloss of starting material. The reaction was quenched by the addition ofwater (4 L) to the reaction mixture. The layers were separated and theaqueous layer extracted with DCM (2×2 L). The combined organic layerswere washed with brine (2×1 L), dried over Na₂SO₄, and concentrated invacuo. The material thus obtained was adsorbed onto a plug of silica geland purified by chromatography (silica gel (60-120 mesh) eluting with agradient of 10-80% EtOAc in hexanes) to provide the title compoundIntermediate 5.8 (1125 g, 3.22 mol, 92%) as a white solid. ¹H-NMR (400MHz, CDCl₃) δ 7.23 (dd, J=2.08, 6.62 Hz, 4H), 6.90 (dd, J=2.12, 6.60 Hz,4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J=7.40 Hz, 2H), 1.33 (t,J=7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: =372.2 (M+Na)⁺.

Biological Activity

[³⁵S]GTPγS Binding

The human APJ receptor was cloned by polymerase chain reaction and thegene encoding the receptor was subcloned in pFLAG-CMV™-3 expressionvector (Sigma, Saint Louis, Mo. USA) in-house at Amgen. A GTPγS bindingassay was performed on membranes prepared from CHO cells stablyexpressing human APJ receptor. The optimum experimental conditions forthe concentrations of GDP, MgCl₂, and NaCl in the assay buffer wereinitially determined. The assay was performed in 9 μL assay buffer [20mM HEPES, pH 7.5, 5 mM MgCl₂, 100 mM NaCl and 0.1% (w/v) BSA], 1 μL ofdiluted test compound (starting with 0.75 mM, 2-fold serial dilutionwith DMSO, total 22 points), 10 μL of 18 μM GDP (final concentration of3 μM GDP), 20 μL of 0.25 μg/m L membrane protein expressing human APJreceptor captured with WGA PS beads (final concentration of 5 μg perwell), and 20 μL of 0.3 nM [³⁵S]GTPγS (final concentration is 0.1 nM[³⁵S]GTPγS)(Perkin Elmer Life and Analytical Sciences, Waltham USA). Onecolumn of the plate was 1 μL of DMSO as background and another column ofthe plate was 1 μL of 180 μM Pyr-Apelin-13 which was used as control ata final concentration of 3 μM. Incubation was at RT for 90 min and themicroplate was read using a ViewLux™ ultra HTS Microplate Imager(PerkinElmer, Inc.). All the results presented are means of severalindependent experiments and analyzed by non-linear regression methodsusing the commercially available program Prism (GraphPad, San Diego,Calif.) providing the EC₅₀ values detailed in Table 3.

The following table includes biological activity data obtained using theprocedures and assays set forth above for the Example compoundsdescribed herein.

TABLE 3 Biological Activity Information for Example Compounds. ExampleActivity hAPJ SPA EC₅₀ IP (nM) 4.0 30 4.1 745 4.2 27 4.3 194 4.4a 2444.4b 193 4.5 11 4.6 20 4.7 78 4.8 86 4.9 193 4.10 Prophetic 4.11Prophetic 4.12 Prophetic 4.13 Prophetic 4.14 Prophetic 4.15 Prophetic4.16 Prophetic 4.17 2.8 4.18 Prophetic 4.19 Prophetic 4.20 Prophetic4.21 Prophetic 4.22 Prophetic 4.23 Prophetic 4.24 1.5 4.25 Prophetic4.26 Prophetic 4.27 Prophetic 4.28 Prophetic 4.29 Prophetic 4.30Prophetic 4.31 Prophetic 4.32 Prophetic

APJ is a G-protein coupled receptor that is closely related to theAngiotensin II Type 1 receptor (AT1R) with 50% homology in thetransmembrane domain. Apelin is a known endogenous ligand for APJ andrecently another ligand named ELABELA has been identified as anotherpotential ligand for the APJ receptor (Tatemoto, K. et al., Biochem.Biophys. Res. Commun., 251, pp. 471-476 (1998); Pauli, A. et al.,Science, 343, pp. 1248636 (2014)). Since its discovery, there isaccumulating evidence indicating the role of the apelin-APJ receptor inthe pathophysiology of cardiovascular diseases. Pre-clinical andclinical studies have shown that acute infusion of apelin or APJagonists improve cardiac function under heart failure settings (Berry,M. F., et al., Circulation, 110(11) pp. 11187-11193 (2004); Japp, A. G.et al., Circulation, 121, pp. 1818-1827 (2010)).

A key emerging aspect of the apelin-APJ system is its interaction withthe renin-angiotensin system. Apelin is also known to counter-regulatethe vasoconstriction actions of AngII. Apelin knockout mice show astrong increased vasopressor response to AngII indicating that theapelin/APJ system exerts the hypotensive effect in vivo against thepressor action of AngII. In addition, the apelin activated APJ pathwayinhibited angiotensin-mediated formation of atherosclerosis throughinteraction with the AT1R (Chun, H. J., et al., J. Clin. Invest., 118,pp. 3343-3354 (2008), Siddiquee, K. et al., J. Hypertens., 29, pp.724-731 (2011), Sim, X. et al., Hypertens. Res., 34, pp. 701-706(2011)). This could be mediated by convergence of two independentintracellular signaling pathways or via direct physical interaction ofAPJ with AT1R to form a heterodimer. Siddiquee et al. showed that theAngII signaling is antagonized through apelin-dependentheterodimerization and APJ mediated negative allosteric modulation ofAT1R function (Siddiquee, K. et al., Br. J. Pharmacol., 168, pp.1104-1117(2013).

We were interested to understand if the heterodimerization of APJ-AT1Rupon activation by APJ agonists would have any beneficial outcomeclinically in heart failure patients considering most of these patientsare on standard of care drugs such as angiotensin blockers (angiotensinII receptor antagonists or angiotensin receptor blockers (ARBs)) andangiotensin converting enzyme (ACE) inhibitors. In order to explore thecross-talk between APJ and the AT1R receptor, we examined IP1 signalingmediated by AT1R upon activation with APJ agonists. Surprisingly andcontrary to the findings by Siddique et al., activation of the APJpathway resulted in positive cooperativity of AngII by shifting itspotency to the left and also increasing the efficacy of the IP response(see methods and results section below). Conversely, blocking the AT1Rreceptor by an ARB such as losartan relieved the inhibition of the APJreceptor and up regulates its signaling which is observed as synergisticeffects in both ex-vivo and in vivo studies. This work establishes a newparadigm for cross-talk interaction/heterodimerization between APJ &AT1R which might have implications for approaches to pharmacologicalinterventions in heart failure populations.

The interaction between acetyl cholinesterase (ACE2) and Apelin biologyis complicated. To investigate the interaction between the Apelin-APJand ACE signalling pathways, we examined the improvement in cardiacfunction with APJ small molecule agonists in the presence of ACEinhibitor captopril in heart failure rats in vivo. Captopril alone,under acute settings, does not show a marked improvement incontractility or ejection fraction acutely. However, in the presence ofan APJ agonist, there was a shift in potency to the left with markedimprovement in contractility and ejection fraction without changes inheart rate. These findings provide a new reference for the understandingof the regulation of ACE2 for the renin angiotensin aldosterone system(RAAS), independent of AT1R signaling and offer new potential drugtargets for the treatment of diseases such as hypertension and heartfailure. This work clearly establishes that combination of an agonist ofthe APJ receptor with an ARB such as losartan and/or with an ACEinhibitor such as captopril which may play an important role inproviding greater efficacy in treating heart failure patients, forexample in improving contractility and ejection fraction withoutchanging the heart rate.

Evidence for Allosteric Interaction Between APJ and AT1R Using IP Assay

Methods

Single and double stable recombinant cell lines were generated for humanAPJ and the AT1R receptor in CHO K1 cells tagged either with FLAG orhemagglutinin (HA) tag. Briefly, the CHO-K1 APJ/AT1R cells were seededin culture medium of DMEM-F12 and 10% FBS at a density of 15 k/well in a96 well plate overnight. The next day, the culture medium was replacedwith medium containing no serum for 4 hours. The compound AngII at arange of concentrations (1 pM-10 μM) with or without differentconcentrations of APJ agonists were diluted in stimulation buffer andadded to the cell plate. The plate was sealed and incubated for 1 hour.This was followed by addition of IP-d2 conjugate followed by europiumcryptate antibody conjugate into the wells. The plate was sealed,followed with incubation for 2 hours at RT. Time-resolved fluorescenceresonance energy (TR-FRET) at 620 nm and 665 nm was measured after 2horns with an Envision reader. The signal ratios and delta F werecalculated and the amount of IP1 produced was inversely proportional tothe TR-FRET ratio, 665/620 nm.

Results

In cells expressing both APJ and the AT1R receptor, addition of APJagonists at different concentrations increased the maximal response ofAngII and also shifted the potency to the left. The increase in IP1response reached a maximal effect both in potency and Emax indicating aceiling effect which is a hallmark for allosteric cooperativity betweenthe AT1R and APJ receptor (FIG. 1). However, this effect ofcooperativity was not observed in either APJ or AT1R recombinant stablecell lines indicating that there is functional cross-talk between thetwo receptors through physical interaction or with downstream effectors(FIG. 2 and FIG. 3). Based on the above findings of cooperativity, werationalized that if an APJ agonist can induce heterodimerization of APJwith AT1R, blocking the AT1R with losartan would enhance the activationof APJ upon addition of small molecule agonists. We observed that APJsmall molecule agonists induced positive cooperativity in the presenceof AngII and addition of losartan relieved this cooperativity andresulted in synergistic effects of enhancing the efficacy of the APJreceptor. This work clearly establishes that combination of an agonistof the APJ receptor with an ARB such as losartan or an ACE inhibitorsuch as captopril may play an important role in providing greaterefficacy in treatment of heart failure patients.

All publications and patent applications cited in this specification arehereby incorporated by reference herein in their entireties and for allpurposes as if each individual publication or patent application werespecifically and individually indicated as being incorporated byreference and as if each reference was fully set forth in its entirety.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R¹ is selected from R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), or R^(1g); R^(1a) is an unsubstituted C₁-C₈ straight or branched chain alkyl or R^(1a) is a C₁-C₈ straight or branched chain alkyl substituted with 1, 2, or 3 R^(1a′) substituents; R^(1b) is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstituted C₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈ cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, 3, or 4 R^(1b′) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with 1, 2, or 3 R^(1b′) substituents, or a monocyclic C₄-C₈ cycloalkenyl substituted with 1, 2, or 3 R^(1b′) substituents; R^(1c) is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R^(1c′) substituents; R^(1d) is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1d) substituents; R^(1e) is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R^(1e) substituents; R^(1f) is a 5- or 6-membered heteroaryl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1f′) substituents, wherein the 5-membered heteroaryl group includes 1, 2, or 3 heteroatoms independently selected from N, O, and S and the 6-membered heteroaryl group includes 2 or 3 N heteroatoms; and further wherein if the 5-membered heteroaryl includes only 1 hetero atom, then it is selected from N or S; R^(1g) is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R^(1g′) substituents; R^(1a′) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₄ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyO—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a monocyclic or bicyclic C₆-C₁₀ aryl group, —O-(monocyclic or bicyclic C₆-C₁₀ aryl group), a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —O-(monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S), C₃-C₈ cycloalkyl, —O—(C₃-C₈ cycloalkyl), —O—(C₁-C₆ alkyl)-(C₃-C₈ cycloalkyl), —O—(C₁-C₆ alkyl)-(monocyclic or bicyclic C₆-C₁₀ aryl group), O—(C₁-C₆ alkyl)-(monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S), a 3 to 8 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —O-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, or S), or an —O—(C₁-C₆ alkyl)-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, or S), wherein the C₆-C₁₀ aryl of any of the R^(1a′) groups that include a C₆-C₁₀ aryl group, the heteroaryl of any of the R^(1a′) groups that include a heteroaryl group, the C₃-C₈ cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈ cycloalkyl group, and the heterocyclyl of any of the R^(1a′) groups that include a heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R^(1a′) substituents; and further wherein the C₃-C₈ cycloalkyl of any of the R^(1a′) groups that include a —C₃-C₈ cycloalkyl group, and the heterocyclyl of any of the R^(1a′) groups that include a heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the S atom of the heterocyclyl of any of the R^(1a′) groups that include a heterocyclyl group may contain one or two oxo substituents, and still further wherein, the heteroaryl of any of the R^(1a′) groups that include a heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; R^(1a″) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl); R^(1b′) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the R^(1b) phenyl and R^(1b) heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R^(1b′) substituents; and further wherein two R^(1b) groups on a single carbon atom of a monocyclic C₃-C₈ cycloalkyl R^(1b) group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S; R^(1b″) is in each instance, independently selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl); R^(1c′) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl), wherein R^(1c′) may also be oxo unless R^(1c′) is a 6-membered heterocyclic group that includes one N atom and includes at least one double bond, and further wherein two R^(1c′) substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R^(1c′) group may join to form a 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 N atoms and may further optionally be substituted with 1 or 2 R^(1c′) substituent and may include an oxo substituent if the ring is not an aromatic ring and further wherein two R^(1c′) substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R^(1c) group may join to form a 5 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 heteroatoms selected from N, O, or S and may further optionally be substituted with 1 or 2 R^(1c″) substituent and may include an oxo substituent if the ring is not an aromatic ring; R^(1c″) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyO—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl); R^(1d′) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1d′) group may optionally be substituted with 1 or 2 R^(1d′ ′) substituents; and further wherein two R^(1d′) substituents on adjacent carbon atoms of the phenyl R^(1d′) group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1d′) substituent and may include an oxo substituent if the ring is not an aromatic ring; R^(1d″) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyO—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl); R^(1d″) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl); R^(1e′) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂; R^(1f′) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), or —CH(OH)-phenyl, wherein the phenyl of the —CH(OH)-phenyl may optionally be substituted with one or two R^(1f″) substituents; and further wherein two R^(1f′) substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of the 5- or 6-membered heteroaryl R^(1f) group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1f′) substituent and may include an oxo substituent if the ring is not an aromatic ring; R^(1f′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyO—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl); R^(1f″) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl); R^(1g′) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₁-C₆ alkyl —OH, —C₁-C₆ haloalkyl-OH, —C₁-C₆ perhaloalkyl-OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —C(═O)-(heterocyclyl), a C₃-C₆ cycloalkyl group or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S; R² is selected from —H, or C₁-C₄ alkyl; R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a′) substituents, an unsubstituted C₃-C₈ cycloalkyl, a C₃-C₈ cycloalkyl substituted with 1, 2, or 3 R^(3a′) substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula —(CR^(3b)═CR^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, -Q, a group of formula —(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h′) substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈ cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R^(3h) substituents; R^(3a) in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3h) in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S; Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl); R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a′) substituents, and further wherein the straight or branched chain C₁-C₆, alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents; R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a′) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, oxo, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —S—(C₁-C₆ alkyl), —S—(C₁-C₆ haloalkyl), —S—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —C(═O)NH(C₃-C₆ cycloalkyl), —C(═O)N(C₁-C₆ alkyl)(C₃-C₆ cycloalkyl), —C(═O)N(C₃-C₆ cycloalkyl)₂, —S(═O)—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a 3 to 6 membered cycloalkyl group, a 3 to 6 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, or S, a phenyl group, or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the a 3 to 6 membered cycloalkyl R^(4b) group, the 3 to 6 membered heterocyclyl R^(4b) group, the phenyl R^(4b) group, and the a 5 or 6 membered heteroaryl R^(4b) ring are unsubstituted or are substituted with 1 or 2 R^(4c) substituents; and further wherein the 3 to 6 membered cycloalkyl R^(4b) group and the 3 to 6 membered heterocyclyl R^(4b) group may optionally be additionally substituted with an oxo substituent; and R^(4c) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂.
 2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1a).
 3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1a) is an unsubstituted C₂-C₆ straight or branched chain alkyl or R^(1a) is a C₁-C₆ straight or branched chain alkyl substituted with 1, 2, or 3 R^(1a′) substituents, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₄ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl).
 4. The compound of claim 3 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1a) is an unsubstituted C₂-C₆ straight or branched chain alkyl or R^(1a) is a C₁-C₆ straight or branched chain alkyl substituted with 1, 2, or 3 R^(1a′) substituents, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl).
 5. (canceled)
 6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1b).
 7. The compound of claim 6 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1b) is an unsubstituted monocyclic C₃-C₈ cycloalkyl or is a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, or 3 R^(1b′) substituents.
 8. The compound of claim 7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1b) is an unsubstituted monocyclic C₃-C₆ cycloalkyl or is a monocyclic C₃-C₇ cycloalkyl substituted with 1 or 2 R^(1b′) substituents, wherein R^(1b) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ perhaloalkyl.
 9. (canceled)
 10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1c).
 11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1c) a 5- or 6-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R^(1c′) substituents.
 12. The compound of claim 10 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1c) a 5- or 6-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R^(1c′) substituents, wherein the substituted or unsubstituted R^(1c) is selected from tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.
 13. (canceled)
 14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1d).
 15. The compound of claim 14 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1d) is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R^(1d) substituents, wherein the R^(1d) substituents are independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), or —S(═O)₂N(C₁-C₆ alkyl)₂.
 16. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1e).
 17. The compound of claim 16 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1e) is an unsubstituted furanyl substituted with 1 or 2 R^(1e′) substituents. 18-19. (canceled)
 20. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1f).
 21. The compound of claim 20 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1f) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 22. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is R^(1g).
 23. The compound of claim 22 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1g) is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 24. (canceled)
 25. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is an unsubstituted C₁-C₁₀ alkyl or is a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a) substituents.
 26. The compound of claim 25 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, or —CH(CH₃)₂.
 27. (canceled)
 28. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula a group of formula —(CR^(3b)R^(3c))-Q. 29-34. (canceled)
 34. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q.
 36. The compound of claim 34 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein, R^(3d) and R^(3e) are independently selected from —H, —C₁-C₆ alkyl, —(C₁-C₆ alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); and R^(3f) and R^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆ alkenyl).
 37. The compound of claim 34 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein, R^(3d) and R^(3e) are independently selected from —H, or —C₁-C₆ alkyl; and R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH, or —O—(C₁-C₆ alkyl). 38-39. (canceled)
 40. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule. 41-42. (canceled)
 43. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyridinyl, phenyl, naphthalenyl, or cyclohexyl any of which may be unsubstituted or substituted with 1, 2, or 3 R^(Q) substituents. 44-48. (canceled)
 49. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(Q) in each instance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl).
 50. (canceled)
 51. The compound of claim 1 the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule. 52-54. (canceled)
 55. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R² is —H.
 56. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridinyl, or pyrimidinyl, any of which may be unsubstituted or substituted with 1, 2, or 3 R^(4a′) substituents.
 57. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(4a) is in each instance independently selected from —F, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl-OH), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆ alkyl)₂. 58-59. (canceled)
 60. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule. 61-64. (canceled)
 65. The compound of claim 1, wherein the compound is selected from

or the pharmaceutically acceptable salt thereof, or the mixture thereof.
 66. The compound of claim 1, wherein the compound is selected from

or the pharmaceutically acceptable salt thereof, or the mixture thereof.
 67. A pharmaceutical composition, comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, and at least one pharmaceutically acceptable excipient. 68-70. (canceled)
 71. A method of treating a cardiovascular condition, the method comprising: administering to a subject an effective amount of the compound of claim 1 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof. 72-112. (canceled) 